THE SYNTHESIS OF HALOGENATED PHTWALONITRILES AND THEIR USE

FOR THE SYNTHESIS OF MONONUCLEAR AND BDWCLEAR

PHTHALOCYANINES.

A thesis submitted to the Faculty of Graduate Studies

in partial fulfillment of the requirements

of the degree of

DOCTOR OF PHILOSOPHY

Graduate Programme in Chemistry

York University

Toronto, Ontario, Canada

May 1997

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THE PEEPARATION OF HALOGENATED PHTHALONITRILES AND THEIR USE IN THE SYNTHESIS OF MONONUCLEAR AND

BINUCLEAR PHTHALOCYANINES

by DMITRZ S. TEREKHOV

a dissertation submitted to the Faculty of Graduate Studies of York University in partial fulfillrnent of the requtrements for the degree of

DOCTOR OF PHILOSOPHY

Permission has been granted to the LIBRARY OF YORK UNIVERSITY to lend or seIl copies of this dissertation. to the

i NATIONAL LIBRARY OF CANADA to microtilm this dissertation

l and ta lend or sel1 copies of the film. and to UNIVERSITY MICROFILMS to publish an abstract of this dissertation

The author reserves other publication rights. and neither the dissertation nor extensive extracts from it may be printed or oiherwise reproduced without the author's wr~tten permission.

ABSTRACT

Six new halogen substituted phthdonitdes were synthesized and characterized including

4,5-diiodophthalonitrile (117e) and 3,4-düodophthalonitriie (117b), the first of a 3 4 -

disubstituted phthalonitrile.

Direct bromination of phthalonitrile (3) using N,N-dibromoisocyanuric acid (120) in

sulfuric acid was closely examined using KPLC. The dependence of the yields of the

brominated phthdonitriles on reaction time and sulfunc acid concentration was

investigated. Five bromosubstituted phthalonitriles, namely, 3-bromophthalonitrile (1 2 1 ),

4-bromophthalonitrile (13), 3,6-, 3,4- and 4,s-dibromophthalonitriles (1 22,123,124)

were isolated fkom the reaction mixture and characterized, including four new

compounds 121-124. Pathways of bromination were investigated utiliang HPLC and

using bromosubstituted phthalonitriles as starting rnaterids. Alternative methods for the

synthesis of phthalonitriles 121 and 124 were developed. Direct bromination of 4-

hydroxyphthalonitrile (1 7b) was investigated under similar conditions.

Six new diakynyIphthalonitri~es were synthesized £iom disubstituted bromo- and

iodophthalonitriles including five new 4,5-diaUcyny~phthalonitnles 132-136 and 3,4-

di(3,3-dimethyl- 1 -butynyl)phthalonitrile (1 50). Phthalonitriles 132-1 36 were used for the

preparation of 2,3,9,IO, 16.1 7,23,24-octaalkynylphthalocyanines 137-141 and their zinc

derivatives 144-148. The condensation of 150 led to the fonnation of the single isomer,

'H NMR studies of these Pcs at different concentrations and temperatures clearly

demonstrate the importance of quoting concentration and temperature values when

reporting 'H NMR spectra of phthdocyanines. The aggregational phenornena between

phthdocyanines moieties was discussed and believed to be the main cause of the

downfield chernicd shift of intemal and aromatic protons with increasing the temperature

or with decreasing the concentration of Pcs in solution.

A new single isomer binuclear 1,3-bis-2'-(9', 1 O', 16', 1 7',23',24'-hexakis(3",3"-dimethyi- 1 "-

butynyl)phthalocyaninoxy)-2-ethyl-2-rnethylpropane (154) was synthesized fiom 1,3-bis-

(3'4'-dicyanop henoxy)-2-ethyl-2-methylprope (73c) and 136. Unusual dependence of

the chernical shifts of the aromatic and interna1 protons of 154 on changes in temperature

2 2 was observed. Another binuclear Pc, bis(7 ,8 , 1 22, 1 32, 1 72, 1 82-hexakis(3~73'-dimethyl- 1 '-

butynyI)benzo[g,l.qJ-5, 1 O, 1 S 7 2 0 - t e t r a a z a p o h 1 ) b e n e (155), was synthesized

fiom tetracyanobenzene (50) and 136. UV-vis-IR and 'H NMR spectra of 155 were

useful in examining its low themial stability.

Atternpt to synthesize a binuclear Pc with an aromatic bridge resolved into the synthesis

of 1,8-bis(2,3 -dicyanophenyl)naphthalene (1 57), 1.8-diaminoanthracene (1 63) and 1,8-

diiodoanthracene (164). A 'H NMR shidy of bisphthdonitrile 157 showed that this

compound exists a s two rotamen with a very high energy of interconversion.

1 sincerely wish to thank my supervisor, Dr. Clifford C. Leznoff for providuig me with

guidance, assistance and the opportunity to pursue this enjoyable project. 1 also thank the

staff and faculty rnembers of the Cherniçtry Department at York Universi% Drs. C. M.

McArthur, P. G. Potvin, A. B. P. Lever, D. N. Butler, B. Khouw and M. Hempstead for

their support and encouragement, as well as our valuable discussions. I am gratefûl for

the fiiendship and motivation of Drs. A. Goel, K. Nolan, P. 1. Svirskaya, D. Drew, Jing Li

and M. Monteiro, and of J. Zadykowicz, A. D'Ascanio, B. Suchozak, and H. Isago.

Finally, I thank my family for their support and understanding.

TABLE OF CONTENTS

...................................... ABSTRACT ................ ...............

............................................................... ACKNO WLED GEMENT S..

...................................................................... TABLE OF CONTENTS

................................................................................ LIST OF TABLES

LIST OF FIGURES ...............................................................................

................................................................ LIST OF ABBREVIATIONS

LNTRODUCTiON

1. Background ..................................................................................................

II. Synthesis of monosubstituted phthalonitriles and tetrasubstihited

............................................................................................. phthaloc yanines

m. S ynthesis of disubstituted p hthalonitdes and octasubstituted

........................................................................ phthdocyanines.

IV. Synthesis of bisphthalonitriles and binuclear phthalocyanine .......................

V. Aggregation of phthdocyanines and their 'H NMR spectra. ........................

........................................................................................ RESEARCH PLAN

RESEARCH AND DISCUSSION

1. SYNTHESIS OF HALOGENATED PHTKALONITRILES

a) S ynthesis of 4,5-diiodophthalonitrile (1 17a) and 3,ediiodophthdonitrile

c) Synthesis of 3-bromophthalonitrile (121) .....................................................

d) S ynthesis of 4.5œdibromophthdonitriIe (1 24) ...............................................

e) Bromination of substituted phthaionitriles .....................................................

II . SYNTHESIS OF DIALKYNYL PHTHALONITREES AND

OCTAALKYNYL PHTHALOCYANINES .

a) Synthesis 4.54iallcynylphthaloniûiIes. 2.3.9.14 16.17232 4-

octaalltynylphthalocyanines and 4.5.diallcylphthdonitriles ........................

b) S ynthesis of 4-iodo-5-(1 '-octyny1)phthaloniûile (1 49) ..................................

c ) Synthesis of 3.4~li(3.3~dimethy 1. 1 -butynyl)phthdonitrile (150) and

1.2.8.9.15. 1 6.22.23scta(3.3.dimethy 1. 1 .butynyl)phthalocyanine(l53) .........

1II.SYNTHESIS OF BINUCLEAR PHTHALOCYANINES .

a) Synthesis of 1.3.bis.2'.(9'. 1 0'. 1 6'. I7I.23l.24 ' . h e x w 1 "-

butynyi)phthaiocyaninoxy)-2-ethyl-2-methylpqme (154) ..........................

b) Synthesis of b i ~ ( 7 ~ . 8 ~ . 1 z2. 1 32. 1 72. 1 82.hexakis(3',3'~dimethY1.1 '.

butynyI)benzo[g.l.q]~5.10.15.20~tetraazaporphyrinyl)[b. flbenzene

(1 55) ............................................................................

C) Synthesis of bisphthdonitriles with aromatic bridges .....................................

NEFFECTS OF CONCENTRATION AND TEMPERATURE ON THE 'H

NMR SPECTRA OF PHTHALOCYANINES ..........................................

EXPERIMENTAL SECTION ........................................................................

............................................................................................. CONCLUSION

REFERENCES .................................................................................................

LIST OF TABLES

Table

Table 1:

Table 2:

Table 3:

Table 4:

Table 5:

Table 6:

Table 7:

Table 8:

The bromination of nitrobenzene (1 18) to 3-bromonitrobenzene (1 19).

The bromination of aromatic compounds with two electron-

withdrawing groups with DBI (1 20).

Retention times of products of bromination of phthalonitrile (3) with

DBI (120). TLC silica gel plates (Kodak), eluting mixture ethyl

acetate: hexane (1 :4).

Retention times of products of bromination of phthalonitrile (3) with

DBI (120). HPLC column Supel Cosil LC8, eluting system methanol :

water. (Ratio Water: Methanol(60:40, 10 min,50:50,20 min,40:60, 10

min), Flow rate 0,5 mL/min, Wavelength of W detector 250 nrn)

The calculated isolation yields of the products of reaction of 3 with

120 in 30% fuming sulfuric acid at different times (minutes).

The yields of the products produced by various reactions of 3 with 120

(1 : 1 ratio) in concentrated sulfuric acid at different times (minutes).

The calculated isolation yields of the products of reaction

of 3 with 120 in 8% fuming sulfunc acid.

The calculated HPLC yields of the compounds produced in the

reaction of brominated phthdonitriles with 120 in 30% fuming

sulfiuic acid.

LIST OF FIGURES

EislEe I!w

Figure 1 Four possible isomers of 2,9,16,23-tetrasubstinited Pcs 5

Figure 2 Pc manocycle 37

Figure 3 The optimum interaction of two Pcs. 39

Figure 4

Figure 5

Figure 6:

Figure 7:

Figure 8:

Figure 9:

Figure 10:

Figure 1 1 :

Illustration to Pc aggregation.

1,11,15,25-tetrasubstituted Pc.

The Mass Spectnim for 1 min reaction of 3 with 120.

A representation electronic spectrum for Pcs 137 - 141

A representation electronic spectnun for Pcs 144 - 148

Two possible isomers of APc that can be prepared fiom

153.

Electronic spectrum for Pc 153.

Electronic specaum of binuclear Pc 154.

Figure 12: The electronic absorption spectnim of the binuclear

phthalocyanine 155 before and after heating. 99

Figure 13: Two possible rotamers of 157. 1 03

Figure 14: Rotodproton conelation experiment for compound 157. 105

Figure 15: Plots of chemical shift of interna1 protons of metal fiee

phthdocyanines, as a function of the log of the

concentration.

Figure 16: Plots of the chemical shifi of the aromatic protons of

metai free phthdocyanines, as a hc t ion of the log of

the concentration.

Figure 17: Plots of the chernical shift of aromatic protons of zinc

phthalocyanines, as a function of the log of the

concentration. 114

Figure 18: 'H NMR chemicd shift of the aromatic protons of ZnPc

148, as a function of the pyrazindl48 ration in CD6 at

Figure 19: 'H NMR chemical shifi of the protons of pymzhe, as a

function of the 148/pyrazine ratio in C a 6 at 27 OC.

Figure 20: Dependence on temperature of the chernical shift of the

intemai protons of metal Eree (3,3-

dimethylbutynyl)~cHz 14 1

Figure 21 : Dependence on temperature of the chemical shift of

intenial protons of metal fkee phthalocyanines

Figure 22: Examples of change of the signals with changing

t emperature

Figure 23: Dependence on temperature of the chemical shift of the

aromatic protons of 153 in niaobenzene-ds .

Figure 24: Dependence on temperature of the chernical shift of the

intemal protons of 153 in nitrobenzene-d5.

Figure 25: Dependence on the concentration of the chemical shift of

the h t d protons of 154 in benzene-d6. 125

Figure 26: Dependence on the concentration of the chemical shift of

the aromatic protons of 154 in benzene-d6. 126

Figure 27: Dependence on temperature of the chernical shüt of the 128

intemal protons of 154 in nitrobenzene-d5.

Figure 28 : Dependence on temperature of the chemical shift of the

aromatic protons of 154 in nitrobentene-d5.

LIST OF ABBREVIATIONS

atm

COSY

DBI

DBU

DMAE

DMF

DMSO

absorbace

elemental analysis calculateci (%)

aqueous

atmospheres

boiling point

broad

Celsius

proton-proton correlation

doublet

doublet of doublets

N,N-dibromoisocyanuric acid

1,8-diazabicycIo[5,4,O]undec-7-ene

2,3-dichloro-5,6-dicyanobenzoquinone

2-N,N-dimethylaminoethanol

N,N-dimethylformamide

dimethylsulfoxide

Electron impact

equivalent

ethyl acetate

e1ectron volts

FAB

g

GPC

HPLC

Hz

NIS

IR

IUPAC

J

K

kl

mm01

mol

*P

MS

nrn

PL

fast atom bombardment

grams

gel penneation chromatography

high performance liquid chromatography

Hertz

N-iodosuccinimide

h h e d

Intemational Union of Pure and Applied Chemistry

coupling constant

Kelvin

kilojoules

multiplet, meten

mass to charge ratio

molecular ion

milligrams

rnilliliters

mi~limoles

moles

melting point

mass spectnim

nanome ters

microlit ers

S

t

TFAA

THF

TLC

TEA

TMS

UV

vis

nuclear magnetic resonance

proton nuclear magnetic resonance

p hthaiocyanine(s)

photodynamic therapy

parts per million

quartet

substituent

sin glet

triplet

tri fluoroacetic anhydride

tetrahy dro furan

thin-layer chromatography

triethylarnine

tetramethy lsilane

ultravio1et

visible

INTRODUCTION

Background

Phthalocyanines (Pcs) are macromolecular compounds with an aromatic 18 pi electron

b e r core in which four isoindoline units are joined by four am nitrogens This structure

is very similar to the naturally occuning porphines (1) shown in Scheme 1. Replacement

of four methine groups in the meso position by four am nitrogens makes phthalocyanines

more stable toward heat and oxidation tha. porphines. Substitution of the macro ring with

four benzo groups makes the pi electron density of the inner core M e r delocalized than

in the porphines. This delocalization causes a shift to lower energy in the electronic

spectrum of phthalocyanine relative to porphines. Intemal hydrogens in the

phthalocyanine ring can be replaced by almoa al1 metals in the penodic table to yield

metalated phthalocyanines.

For years metal-fiee and metal-containing phthalocyanines ( ta and 2b) have been a

subject of numerous investigations [l-31. Pcs 2b and many of its substituted derivatives

have found wide practical use as dyes [1,2]. Physicd and chernicd investigations deal

with electrical [46 ] , catalytic [1,2] and electro catalytic [7-91 activities as well as

sensitizer properties [ 1 0,111 and photovoltaic effects [1 2- 1 51. More recently attention to

phthalocyanines as potential second generation drugs in photodynamic therapy of cancer

has generated new interest in the development of novel substituted phthalocyanines [16-

191.

Scheme 1

The unsubstituted metai fiee phthalocyanine (Za) is a very insoluble compound. It

dissolves ody in sulfunc acid. To increase solubility and rnodify the chemical and

physicd properties of phthalocyanines, a number of substituted metai fiee and metalated

phthalocyanines was synthesized.

Direct electrophilic substitution of phthalocyanine leads to mixtures of rnany possible

isomers. This method is used to produce polyhalogenated metal phthalocyanines. For

example, unsubstituted PcCu is converted to hexadecachloro PcCu (phthalocyanine

green) [20]. PcZn can be converted to tetrasulfonated PcZn by direct sulfonation of

unsubstituted PcZn [21]. The biggest problern of such reactions is the fact that impurities

cannot be separated. In the case of hexachloro CuPc, other polychloro phthalocyanines

with 15 or fewer chlorine atoms are fonned and have the same solubility as the desired

product. In the case of tetrasulfonated PcZn, sulfonic acid groups are randomly located

over al1 the benzo groups of the phthalocyanine ring and the isomenc Pcs mixture is

inseparable.

The most commonly used method to synthesize phthdocyanines employs phthdonitde

(3) as a precursor. In this case, four molecules of phthalonitx-ile can be tetramerized under

basic conditions or 3 cm be converted into 1,3-diiminoisoindoline (4) and then four

molecules of 4 can f o m a phthalocyanine ring [22,23]. In both cases, a subsequent two

electron reduction is necessary to aromatize the ring. Other denvatives of phthalic acid

can also be used to form phthalocyanine. The very first synthesis of phthalocyanine

involved the reaction of o-cyanobenzamide (5a) in refluxing ethanol fiom which metal

free phthalocyanine was recovered in a low yield [24]. Phthalic acid (5b) can be treated

with a metal salt as a template at temperatures above 200 OC to form metalated Pcs. The

limibîion of this method is that ody metal Pcs can be synthesized.

Synthesis of monosubstituted phthalonitdes and tetrasubstituted phthalocyanines.

A wide variety of metal-fiee and metal phthalocyanines substituted at the 2,9,16?23- and

1,8,1522-positions of the phthalocyanine ring have been prepared. The synthesis of a

1,8,15,22- tetrasubstituted phthalocyanine begins with the preparation of a 3-substituted

phthdonitrile. The 3-nitrophthalonitrile (6a), now commerciaily available, is a precursor

widely used for such synthesis. Treatment of 6a with K2C03 and N d O 2 in DMSO at

reflux for 0.5 h. led to 3-hydroxyphthalonitrile (7a) in 43% yield. Similarly, treatment of

6a with neopentanol(2 J-dimethyl- 1 -propanol) and K2C03 in DMSO at room

temperature for six days gave 3-neopentoxyphthalonitrile (8a) in 63% yield [25]. Long

reaction t h e s were necessary to drive the reaction to completion, probably due to steric

hiadrance of the substituent at the 3-position and the bullcy alcohol used. Phthdonitrile Ba

was converted to its diiminoisoindoline (9a). Condensation of 9a at 150 OC in 2-N,N-

dimethylarninoethanol (DMAE) gave 1,8,15,22-tetraneopentoxyphthalocyanine (10) in

16% yield as a mixture isomers. If the phthdonitrile 8a was condensed at room

temperature only the 1,8,15,22-isomer was formed [26] (Scheme 2). Similar

transformations can be performed with 4-nitrophthalonieile (6b). This starting material

Figure 1. Four possible isomers of 2,9,l6,23-tetrasubstituted Pcs.

NH3, MeONa C---

MeOH R'

R = OCH2C(CH3)3 1 O

Scheme 2

has less steric hindrance and is more reactive toward nucleophilic substitution reactions.

CALkoxy and 4-benzyloxy derivatives of phthdonitrile were synthesized under

conditions sirnilar to those for the 3-substituted phthalonitriles [27-321. There is only one

report about reaction conditions fiom phthalonitdes that wouid lead only to the pure

2,9,16,23-isomer [32]. Separation of the four possible isomers show in Figure 1 is very

difficult and time consirming. Only recently, was there a report of complete separation of

al1 isomers using HPLC. It took more then a year to achieve this remarkably difncult task

[IO].

The nitro substituent in compounds 6a and 6b undergoes nucleophilic replacement with

amino compounds. Thus, with dimethylamine and piperidine in N,N-dimethylfomiamide

@MF) 6a and 6b produced high yields of the correspondently substituted

aminophthalonitriles [33]. Nitrophthalonitriles c m be reduced to 3- and 4-

aminophthalonitrile (1 la and 1 lb). Reduction of 6a is more difficult than of 6b [34,35].

Compounds 1 l a and I l b can be allcylated. The presence of diailqlamino groups in the

benzene ring of phthalocyanines , d i k e amino groups [3 61, increases their solubility in

organic solvents as compared to the unsubstituted phthalocyanines. They are readily

soluble in DMF, dimethylsulfoxide (DMSO), md quinoline as well as in concentrated

HCI. Their solubility in mineral acids has been used in a number of cases for purification

of these compounds. Metal complexes of aminophthalocyanines were synthesized nom

phthalonitriles by their reaction with metai salts, anhydrous urea and catalytic arnounts of

ammonium molybdate in quinoline at 200-205 OC in 25-55% yields [33]. Amino groups

in compounds 1 la and I l b were converted into diau, groups and then replaced with

iodine or bromine substituents to give 3- and Ciodophthalonitriie (12a and 12b) [34,35]

or 4-bromophthalonitriie (13) [33] (Scheme 2). Another interesting transformation of 4-

diazophthalonitrile to 4-fmocenylphthalonitrile was hvestigated by K. Nolan in our

group [37]. On the other han& it was found that it was impossible to transform 3-

diazophthalonitrile into the 3-ferrocenylphthalonitrile. This fact correlates with the poorer

reactivity of the 3-substituted denvatives of phthdonitrile compared to Csubstihited

phthdonitriles. The compound 6b can be converted to l l b using SnC12, but it was

necessary to use catalytic reduction with Pd as a catalyst to convert 6a into Ila.

Another very common method to produce substituted phthdonitriles and their

corresponding phthdocyanines is to start fiom a substituted phthalic acid (Scheme 3).

Until recently 3-nitrophthdonitnle was not commercially available, and in our group we

had to make it ourseives fiom 3-nitrophthalic acid (13a). The acid 13a was converted into

the ammonium salt and, subsequently, by pyrolysis at a temperature of 230-240 OC into

3-nitrophthdimide (14a). Phthdonitrile 6a was synthesized in two steps. First, ring

opening with aqueous ammonium hydroxide Ied to phthalamide 15a, and then 6a was

obtained by dehydration with trifluoroacetic anhydride in pyridine and dioxane. The 3-

trifluoromethylphthalic acid (13b) was converted to 3-trifluoromethylphthalimide (14b)

by heating with urea. As mentioned before, the diamidophthalic acids are usually formed

fiom the phthdimides by action of aqueous ammonia. However, it was not possible to

convert in this way 14b into the 3-~fluoromethylphthalamide (15b). This compound was

synthesized by action of liquid ammonia on the corresponding phthdimide. Phthdonitrile

16b was obtained by heating the diamide with phosphorus oxychloride in 69% yield. The

corresponding 4-tnfluoromethylphthalonitrile (16c) was produced by the method

mentioned above fkom 1,2dibromo-4-trifluoromethylbenzene (16a) in 3 1 % yield [3 81.

Using the same multi-step reaction, Ctert-buty l- (16d) and 4-nimethy lsily lphthalonitrile

(Me) were synthesized [39].

Substinited phthalonitriles can be synthesized not only fiom aromatic compounds. An

excess of 3,3,3-trifluoropropyne (17) reacted with 2,3-dirnethylbutadiene (18) to form the

cyclic diene (19) in 80% yield. The conversion of 19 by using 2,3-dichioro-5,6-

dicyanobenzoquinone (DDQ) (20) to the benzene derivative 21 was carried out

quantitatively in benzene. Chromium trioxide in a mixture of acetic and sulfuric acid was

used to oxidize 20 into 4-trifluoromethylphthaiic acid (13c). Then, a previously descnbed

sequence of reactions was used to convert phthdic acid into 4-

~fluoromethylphthalonitri1e (16c) [40]. An alternative synthesis of 16c by the reaction of

17 with 2,3-dicyanobutadiene (22) was not very successfiù. The cyclic diene 23 was

obtained only in 10% yield, rnost of the reaction product being the dirner of 22

(Scheme 4).

1. NHjOH or NH3 @COOH 2. Heat (230-240 CC)

_____)

R' COOH R' R R

Ma R=Na, R'=H 13aR=N@, R'=H Mb R=CF3, R' = H l3b R=CF3, R '=H M c R = H, R'=CF3 l3c R=H, R' =CF3 I 14d R = H, R' = C(CH3)3 13d R = H, R' = C(CH3)3 OH aq. or NH3 14e R = H, R' = Si(CH3) 13e R = H, R' = Si(CH3)3

SOC12 or POC13 in DMF, or TFAA, Py, Dioxane

c--.--

Scheme 3

Other important starting materials for the synthesis of the substituted phthdonitriIes are

halogen substituted derivatives of phthalic acid. Coupling of 4-iodophthalonitnle (12b)

with trimethylsilylacetylene (24a) or 3,3-dimethyl- 1 -butyne (24b) gave 4-(2-

(2%) both in 75% yield [35]. Sirnilarly, treatment of 12b with 3-N,Ndiethylamimprop-

1-yne (24c), bis(ûiphenylphosphine)palladium dichlonde and copper O iodide gave 443-

N,N-cüeylaminoprop 1 -ynyl)phthdonitrile (25c) [4 11 (Scheme 5).

Scheme 5

Diethyl esters of 3- and Ciodophthalic acids (26a and 26b) were reacted with copper

trifluoromethanethiolate. The esters 27a and 27b were converted into the corresponding

amides 28a and 28b by heating in an autoclave with liquid ammonia. Phthdonitriles 29a

and 29b were obtained fiom the products of this reaction by the action of phosphorus

oxychloride in pyridine 1381 (Scheme 5).

Tetrasubstituted phthalocyanines have found a variety of applications in electrochemistry,

physical chemistry and biology. The use of one or another phthalocyanine d l y

depends on how easiiy it can be synthesized. The best candidates for commercial use

must be made in one or two steps. Nitro-substituted phthalonitriles 6a and 6b now are

commercially available, and this creates a wide variety of applications for the direct

preparation of denvatives of this cornpound for use in Pc synthesis (for exarnple

tetrahydroxyphthalocyanines [32]). The synthesis of halogenosubstituted phthalonitnles is

a multi-step process and, due to this fact, the synthesis of many teeasubstituted

phthdocyanines is a very complicated and low yield process. Easier and high yield

syntheses of halogenated phthalonitriles will create many possibilities for the synthesis of

new phthalocyanines.

Tetrasubstihited phthalocyanines (having one substituent in each benzo group), with few

exceptions, are synthesized as mixtures of isomers. This is not acceptable for some

applications. For example, for medical applications a mixture of isomen cannot be used.

Pbarmaceutical approval for new dnigs requires that an individual compound be prepared

and not a mixture of isomers. This fact is one reason why much signifiant work is

conducted on the separation of the isomers as well as on synthesis of single isomer

tetrasubstituted Pcs. Unlike tetrasubstituted Pcs, octasubstituted Pcs, which exist as one

isomer, can readily be made.

Synthesis of disubstituted phthalonitriles and octasubstituted phthalocyanines

There are four possible isomers of a disubstituted phthdonitrile: 3,4- , 3 3 - ,4,5- and 3,6.

Two of them 3,4 and 3,5 are not symmetrical and therefore, are capable of forming

mixtures of phthaiocyanine isomers. Another two, 43- and 3,6-, are symrnetrical and can

fonn only one isomer. Most of the work for the synthesis of octasubstituted

phthdocyanines uses these two latter isomers as starting materials.

2,3,9,10,16,17,23,24-Octasubstituted phthdocyanines are most commonly prepared

directly from 4,s-disubstituted phthdonitriles or fÎom 4,s-disubstituted isoindolines

(products of the reaction of ammonia with the corresponding phthalonitriles).

The preparation of 4,s-disubstituted phthalonitriles usudly requires multi-step syntheses

resulting in low overall fields. Typically, one of the steps involves replacement of two

halogens with cyano groups using CuCN. Commonly, in this reaction a monocyano-

monohalogeno by-product is fomed and a high temperature of reaction is required to

achieve completion. Other possible by-products of such reactions are Cu phthdocyanines.

Low yields, high temperature of reaction and difficulties of separation fiom by-products

are limiting the use of 4,s-disubstituted phthalonitriles in phthalocyanine synthesis.

There are only a few approaches to the sathesis of 4,5-disubstituted phthaloniîriles. The

synthesis of a 4,5-dialkoxyphthalonibile usually starts fiom reactions involving the

modification of catechol(30) [42] (Scheme 6). Subsequent bromination of a catechol

diether (31) to give a dibromocatechol diether

Scheme 6

(32), followed by cyanide displacement of the brorno groups ushg copper(1)cyanide in

refluxing DMF, yielded the requued phthalonitrile 33 in 14% overall field. The

octanbstituted phthdocyanines were readily prepared by the cyclotetramerization of the

phthalonhile 33 in refluxing 1-pentanol, catalysed by lithium 1-pentoxide. It was

reported that the use of this method to prepare the long chah alkoxysubstituted Pc fiom

the phthalonitrile had resulted in partial transetherification of the side chahs by the

pentanolate anion and thus, the formation of a mixture of Pc products [47]. Triethylene

glycol mono-methyl ether (3,6,9-trioxadecan-14) can be used as solvent to prevmt

transetherification. A similar chernical pathway to synthesize the corresponding dodecyl

derivative was used by Simon to give 4,s-didodecyloxyphthalonitrile (33) [43]. The 1,3-

diirninoisoindoline derivative (34) was prepared by treating the phthalonitrile with

arnmonia in methanol in the presence of a catalytic amount of sodium methoxide. Finaily,

the diiminoisoindoline derivative was aansfomed into a comesponding substituted

phthalocyanine (3 5) in 2-N,N-dimethylaminoethanol (DMAE) under reflux [43].

The nrst octaalkylphthdocyanine synthesized was (CH,),PcCu reported in 1934, starting

fiom 1,2-dibromo-4,5-dimethylbenzene [45]. The 4,5-diakyIphthalonitriles c m be

synthesized in three steps starting &om O-dichlorobenzene (36) (Scheme 7). This latter

compound reacted with dodecylmagnesium bromide in THF in the presence of a

phosphine-nickel complex to give O-bis-dodecylbenzene (37). The dialkylated compound

is converied into 1,2-dibromo-4,5-di-dodecylbenzene (38) with bromine in CH,Cl,. The

bromo derivative is transformecl into the dicyano wmpound (39) by treatment with

cuprous cyanide in DMF in 5% overali yield. Octa-aikylphthalocyanine (41) was

synthesized fkom the diiminoisoindoline derivative of this phthdonitrile (40) in 25%

yield [43]. H. Nishi and K Kitahara have reported the synthesis of 4,S-diheptanyl,

dinonyl, diundecyl and ditridecylphthalonitriles with overall yields of 3O,2Z, 23 and 38%

respectively using the same procedure. la this research a new synthesis of dialkyl

phthdocyanines was described. Cychtion of 4,5-diallcylphthalonitriles in the presence

of 1,8-diazabicyclo[5,4,O]undec-7-ene @BU) gave 2,3,9,lO, 16,I7,23,24-octaallcyl Pcs or

their copper complexes [Ml. More recently 4,5-diaUqlphthalonitriIes were synthesized

Scheme 7

using a similar approach. In this work, copper and nickel complexes of substituted Pcs

were prepared in two ways. The substituted phthalonitrile was condensai in the presence

of DBU with CuBr2 or NiBr2 in pentan-lsl or the same compounds were synthesized

when diiminoisoindoline derivatives were treated with a nickel or coppa salt in DMAE

146 1.

hother route to synthesize 4,S-disubstituted phthalonitriles is shown in Scheme 8.

Bromination of O-xylene (42) to 1,2-dibromo-4,5-dimethylbenzene (43) and side chah

bromination of 43 gives 4,s-bis@xomomethyl]-l,2-dibromobenzene (44). The reaction of

compound 44 with sodium alkoxides in the corresponding alcohols or with sodium

phenoxide in ethano 1, respectively, af5ords 4,5-bis[alkoxymethyl]- (45a-d) or 4,s-

bis [phenoxymethyll- l,2-dibromo benzenes (45e). These compounds are converted into

the corresponding O-dinitriles (46a-e) by reaction with a srnaII excess of copper(I)

cyanide in DMF. The substituted 1,3-diiminoisoindolines 47a-e were obtained in nearly

quantitative yield fkom 46a-e by passing a Stream of gaseous ammonia through

methanolic solutions. The metal-fiee octasubstituted phthalocyanines 48a-e were

obtained in 70-85% yield by heating 47a-e in refiuxing DMAE for 7 hours and was

purîfied by extraction [48]. Metal phthalocyanines 49a-e were synthesized directly fiom

phthalonitriles 46a-e by heating at 190 O C in ethylene glycol with metal oxides or salts

[NI. Opticall y active phthalocyanines were synthesized starting from 44. Compound 44

reacts with an optically active alcohol to give 4,S-di-[S-(4-dodecyloxy)-2-oxa-pentyl]-o-

MO or MC12, glycol, 190 OC

49

M = Pb, Ni, Co

Scheme 8

dibromobenzene (450. Octanibstituted phthalocyanine 48f was synthesized fiom

phthdonitrile 46f using the above procedure (Scherne 8) [SOI. Other optically active

phthalocyanines were synthesized by Kobayashi et al. [51]. In their work, optically active

(-)-(S)- and (+)-R-22'-dihydroxy-I, 1 '-binaphthyl were condensed with 44 to give

optically active dibromo derivatives 45g. Subsequent treatment of 45g with CuCN in

DMF results in the optically active Cu phthalocyanines (49g).

A number of 4,s-disubstituted phthaloniûiles were synthesized starting fiom 1,2,4,5-

tetrac y anobenzene (50) or benzene- l,2,4,5-tetracarboxy lic acid dianhydride (5 1) (Scheme

9). Compound 50 was treated with arnmonia in pentanol in the presence of sodium

pentoxide to give the dicyano-diimino denvative (52). Condensation of 52 in reflwing

DMAE gave the octacyanophthalocyanines (53). The cyano groups cm be hydrolyzed to

produce octacarboxyphthalocyanine (54). Compound 53 can be modified into a number

of symmetrically substituted phthalocyanines (55,56,57) as shown in Scheme 9 [52].

A series of 1,4,8,11,15,18,22,25-octaalkylphthalocyanines were synthesized fiom furan

(58) (Scheme 10). Furan 58 was treated with n-butyl lithium and then with brorno

*es to give 2,5-diakylfurans (59). Compound 59 was converted into 3,6-

diakylphthalonitrile (61) in a one-pot reaction. The progress of the initial Diels-Alder

reaction was monitored by NMR spectroscopy. Once the mixture had reached

equilibriurn, the reaction was cooled and base was added.

Scheme 9

Scheme 10

Phthdocyanines 62 were obtained via condensation (LiOCsHl ,, C5Hl ,OH) of 61 and rnetalated using Cu(OC,H,,), to produce Cu phthdocyanines (63) [SS].

The l,3,8,lO, 15,17,22,24-octasubstituted phthalocyanines were prepared kom 3 3 -

disubstituted phthalonitriles (for example [54] 3,5-dinitrophthalonitrile). These

compounds exist as a mixture of four possible isorners. There are no data in the literature

about synthesis of 1 J,8,9,lS, 16,22,23i~=tasubstituted phthalocyanines or 3,4-

disubdtuted phthalonitriles.

Syntheses of disubstituted phthalonitriles are complicated multi-step processes with low

overall yields. Octasubstituted phthalocyanines would be used much more widely if they

were easily synthesized fkom starting materials such as nitrophthalonitriles as for the

tetrasubstituted phthdocyanines (6a, 6b). Unfortunately, only one dinitrophthdonitrile is

known (3,5-dinitrophthalonitrile) and the synthesis of tbis compound is complicated.

Moreover, 3,s-dinitrophthalonitrile is not very stable (it decomposes readily by heat).

DihalogenophthalonitriIes are unknown. Substituent groups are introduced into the

benzene ring pnor to nitrile group formation. This procedure narrows the number of

substituents to those that tolerate high temperature. The 3,4-disubstituted phthalonitriles

are unknown and successful synthesis of 3,4-dihalogenophthalonitrile cm help to

investigate properties of the new 1,2,8,9,15,16,22,23~octasubstituted phthalocyanines.

Synthesis of bispbthalonitriles and binuclear phthalocyanines.

The four-electron reduction of oxygen into water using cofacial dicobalt porphyrùis was

reported by different groups of researchers [55,56]. The cofacial structure had been

achieved either by using a cyclophane type of fiamework [55] or by covalently linking

two porphyrins on ngid spacers, via the 1,8-positions of anthracene and biphenylene [56].

Binuclear porphyrins are sensitive to Light, oxygen, or both, and tend to lose their

catalytic activity with t h e . Since phthdocyanines are more stable than porphyrins,

binuclear phthalocyanines were synthesized for electrochemical shidies. Porphyrins have

mes0 methine groups that can be comected to the spacer to make binuclear porphyrh. A

different approach is required for synthesizing binuclear phthalocyanines. These

compounds are the result of mixed condensations of bisphthalonitriles and

phthalonitriles. Usually, the phthalonitrile is used in large excess in order to prevent self-

condensation of the bisphthalonitrile. The yields of bhclear phthalocyanines are low and

the main product of the reactions are mononuclear phthalocyanines - the product of self

condensation of the phthalonitrile. Bisphthdonitriles are cornpounds where two

phthalonitriles are linked through the 3- or 4-positions of the benzene ring. A spacer

group c m be as flexible as a hetero atom, an alkyl chah or an akyldiol, or it can be ngid

like naphthalene, anthracene or an alkene. Another class of binuclear phthalocyanines is

one where two phthalocyanine rings share aromatic or polyaromatic groups. In these

compounds the macromolecular rings are planar, and the aromatic system of the hKo

phthalocyanines is linked through a spacer group. Macro rings in the binuclear

phthalocyanine can be directly Linked to form the so called "-1 "-linked binuclear

phthalocyanines.

In a way similar to the synthesis of substituted phthalocyanines, the synthesis of binuclear

phthalocyanines starts nom the prcparation of bisphthdonitriles. For such syntheses

halogen substituted or nitrophthalonitriies are used for reaction with the bndged group.

Treatment of 6b with Ctert-butylcatechol(64) or catechol(31) and anhydrous potassium

carbonate in dry DMF at room temperature for 36 h gave 4-tert-butyl-12-bis-(3,4-

dicyanophenoxy)benzene (65) and 1 ,2-bis-(3,4-dicyanophenoxy)bentene (66) in 84 and

78% yields, respectively (Scheme 11) [35]. Compounds 65 and 66 were converted to

their respective 1,3-diiminoisoindolines (67a, 67b) using the above procedure.

Condensation of 67a with 5-neopentoxy-1,3-diirninoisoindolines (68) in DMAE for 60 h

gave a green-black solution, which was diluted with water to give a blue coloured

residue. Flash chromatography of the residue, taken up in toluene, yielded in the first

fiactions using toluene as eluent, 2,9,16,23-tetraneopentoxyphthalocyanine (69), the

product of self condensation of 68 in 58% yield. Further elution with toluene gave a

mixture of 69 and Ctert-butyl- l,2-bis-2'-(9', 16',23'-trineopentoxyphtha1ocyaninoxy)-

benzene (70a) and some later fiactions of pure 70a as sbining dark purple plates. Repeti-

tive flash chromatography of the mixed fhctions 69 and 70a gave pure 70a in 13% over-

al1 yield. In this reaction mixture, traces of trinuclear phthalocyanine were also found.

70a R = tert-butyl 70b R = H 67a R = tert-butyl

67b R = H

71a R = tert-butyl 71b R=H

Scheme 11

The above synthesis was subsequently repeated but using catechol as the bndging p u p .

The yields of mononuclear phthalocyanine 69 and binuclear 70b were 42 and 10%

respectively. Phthalocyanine dimers 70a and 70b were readily converted to their dicobalt

(II') derivatives 71s and 71b.

SymmetricaI diols 72a, 2,2-dimethyl- 1,3-propanedi01 (72b), and 2-ethyl-2-methyl- 1,3-

propanediol(72c), reacted with more than two quivalents of 6b and &CO3 in DMSO to

give 1,3-bis(3',4'-dicyanophenoxy}-2-methyl-2-Ioxeylpropane (73a), 1,3-

bis(3',C-dicyanophenoxy)-2,2-dimethy1propane (73 b), and 1,3-bis(3'4'-dicyanophenoxy)-

2-ethyl-2-methylpropane (73c) respectively (Scheme 12). Bisphthdonitriles 73b and 73c

were ccnverted to their bisisoindolines 74b and 74c, as previously and used in subsequent

condensations without M e r purification. Heating the bisisoindolines 74b and 74c at

150 O C with a large excess of 68 in DMAE for 24 h yielded a mixture of mononuclear

phthalocyanine 69 and binuclear phthalocyanines 7Sb and 7% in 17 and 10% yields,

respectively. On the other hand, bisphthdonitrile 73a was condensed with 4-

neopentoxyphthalonitrile (8b) using cuprous cyanide in DMF. This method produced Cu

mononuclear 69 and di Cu binuclear phthaiocyanine 75a in only 3 1 % and 1 % yields,

respectively. Metal-fiee binuclear phthalocyanines were readily converted to di Cu and

Co derivatives 76b and 76c in high yields (54.74%) [30].

Scheme 12

Condensation of 6b also gave bis[3,4-dic yanophenyI]ether (77) (Scheme 1 3). Treatment

77 with ammonia gas yielded bisisoindoline 78. Mixed condensation of 78 and 68 gave

mononuclear 69 and binuclear phthalocyanine 79 linked by a single atom bridge with

yields between 11 and 2%. Some trinuclear phthalocyanine was also produced during this

reaction with yields h m 4 - 6.6% [57]. To optimize yields of binuclear phthdocyanines

and prevent the synthesis of polynuclear phthdonitriles, the ratio of phthdonitrile to

68, DMAE

Scheme 13

CIodophthalonitde (12b) was used for the preparation of bisphthdonitriles linked by

chains of carbon atoms. The dicoupling of 12b with acetylme (80) gave 1 f -bis-(3,4-

dicyanopheny1)ethyne (81) in 90% yield. A suspension of 82 in acetonitrile was

hydrogenated for 4 h at room temperature over 10% palladium on charma1 to give, in

83% yield, 1,2-bis-(3,4dicyanophenyl)ethane (82). Compound 82 was convertcd to its

1,3-diiminoisoindoline 83 and condenseci with an excess of the diiminoisoindoline 68 to

give large amounts of rnononuclear phthdocyanines 69 and binuclear phthalocyanine 84

in 10% yield 1351 (Scherne 14) [30].

4-Iodophthalonitrile (12b) reacted with trimethylsilylethyne (24) to give compound 85

(Scheme 14). Oxidative coupling of 85 yielded bisphthdonitrile 86 in 76% yieid.

Catalytic hydrogenation of 86, as shown before, gave 1,4-bis-(3,4=dicyanophenyl)butane

(87) in 84% yield. Conversion of 87 into its bis-l,3-diiminoisoindoline (88) and

subsequent rnixed condensation with 68 gave monomer 60 and the tetramethylene

btidged dimer 1,4-bis-2'-(9', l6',23 '-trineopentoxyph~alocyaniny1)butane (89) in 1 -4%

yield [30].

Al1 of the previously descnbed binuclear phthalocymines did not have h e d cofacial

positions between the two phthalocyanine rings. Four-electron reductions of oxygen to

water using cofacial dicobalt porphyrins have been reported. The fixeci stnicture was

achieved by covalently linking two porphyrins on a ngid spacer, via the 1,8-positions of

anthracene and biphenylene [56]. In order to prepare binuclear phthdocyanines rigidly

linked by a polyaromatic spacer, two bisphthdonitriles were synthesized. The mixed

condensation of 12b and 1,8&odonaphthalene (90) using activated elemental nickel at

room temperature for 3.5 h gave the desired 1 ,8-bis(3,4-

R = 0CH2C(CH3)3 1 ;;(OAcheH20 M = Hz, Co

P C H Z W ~ G H ~ P ~ H ~ ( R ) ~ HN

89 68, DMAE

+ N

H t N 69

88

Scheme 14

3 1

dicymopheny1)naphthalene (91) in 15.5 % yield. Compound 91 was converted to its 1,3-

diiminoisoindoline (92) and subscquently condensed with 68. Purification of the reaction

mixture by flash chromatography followed by vacuum liquid chromatography gave the

mononuclear phthalocyanine 69 and the binuclear phthalocyanine 93 in 45 and 8.7%

yields respectively (Scheme 15). The binuclear phthalocyanine 93 was converted to its

dicobait 94, dicopper 95 and dizinc 96 derivatives [59]. Treatment of 1,8-

dichloroanthracene (97) with Lithium and zinc bromide in dry THF at O OC with

ultrasonic activation for 2 h generated the 1,l-organozinc interinediate (98). A cross-

coupling reaction between 12b and 98 catalysed by

tetrakis(ûiphenylphosphine)palIadium gave 1,8-bis(3,4-dicyanopheny1)anthracene (99) in

9.9% yield. This synthesis shows the advantage of the cross-condensation method

compared to the rnixed condensation method. The diaryl cross-condensation reaction

produced only one product. Therefore, purification of the reaction mixture was much

easier. The yield of the desired product of such a reaction is higher. Attempts were made

to use the cross-condensation for the preparation of 92, but only 1-(3,4-

dicya.nophenyl)naphthaiene was produced, probably because of the small distance

between the 1 and 8 positions in 1,8-diiodonaphthalene and the ability of zinc to produce

diaryl derivatives [60]. Compound 99 was converted into its 1,3-diiminoisoindoline (1 00)

and condensed with 68 to give a mixture of mononuclear (69) and binuclear

phthdocyanines (101). The mixture was purified by flash chromatography to rernove the

main amount of mononuclear phthdocyanine and then a trace of 69 was removed by gel

IO0

Scheme 15

penneation chromatography to give binuclear phthalocyanine 1 0 1 in 1 2% yield. Metal-

fkee binuclear phthalocyanine was converted to its dicobalt I O2a and dizinc 1 O2 b

derivatives by a previously described procedure.

Ano ther class of binuclear p hthalocy anines is the so-called planar binuclear

phthdocyanines. In these compounds two phthalocyanine rings are linked together into

the one big system with an arornatic bridge (Scheme 16). Compound 51 was converted

into its diiminoindoisoline (103). A mixed condensation of 103 with 68 in refluxing

DMAE under argon gave binuclear phthalocyanine 1 O4a after flash and gel pemieation

chromatography [58]. The dicobalt derivative 104b was prepared by heating metal free

104a in DMF with CoCI,. Since the structure of these compounds lacks a benzene ring

relative to the other lcnown binuclear phthdocyanines, this is referred to as the (-1) linked

binuclear p hthalocyanine (Scheme 1 6). S ynthesis of (- 1)lioked binuclear phthaloc yanines

can be achieved in two steps. In this case, two different substituted phthdocyanines can

be put into rings (Scheme 16). A mixed condensation of compound 52 and 4- te~-

butylphthalonitrile (105) in refluxing DMAE Ieads to mononuclear phthdocyanine 106.

Compound 1 O6 then reacted with 2-tert-butyl-5 ,7-diimino-6HHpyrrolo[3 ,4-b]-pyrazine

(107) to give binuclear phthalocyanine 1 O8 [60].

I04a M = Hz, R = 0CH2C(CH3)3, X = C 1046 M = Co, R = 0CH2C(CH3)3, X = C 108c M = Cu, R = C(CH3>3, X = N

Scheme 16

Most of the binuclear phthalocyanines are synthesized as a mixture of isomers. A

tetrasubstituted phthalocyaaine having 4 identical substituents (one in each benzo ring),

can con& of 4 possible isomers. An isomeric mixture of binuclear phthaiocyanine cm

achially con& of 36 isomm. Of course, separation of such a mixture into individual

compounds is impossible. Proton NMR spectra of such a mixture will have a few broad

peaks as representative of protons of the each of the isomers. Therefore, the information

that cm be obtained from the NMR spectroscopy is very limiteci. The synthesis of a

single isomer binuclear phthalocyanines would help us to understand aggregational

p henomena of phthaloc yanines and binuclear phthaiocy anines in p articular.

Aggregation of phthalocyanines and their 'H NMR spectra.

Aggregation is a well-known phenornenon in phthalocyanine and porphyrin chernistry

[6 1-63]. Strong attractive interactions between two phthalocyanine rings lead to their

aggregation in solution [64]. Both in solution and in crystals, the two phthdocyanines

adopt a cofacial arrangement with their centres offset. This geometry may be summarized

as follows:

1. The x-systems of two neighbouring phthalocyanines are parallel, with an interplanar

separation of 3.4-3.6 A.

2. The x-stacked phthalocyanines are not rotated relative to one another, Le., their

nitrogen-nitrogen axes (x or y axes in Figure 2) are parallel.

3. One phthalocyanine is offset relative to the 0 t h by 3-4 A along the nitmgen-nitmgen

Figure 2: Pc macrocycle.

The magnitude of the tr-interaction is enhanceci by phthalocyanine metalation, but its

geometry is unaitered [64]. The greater the intrarnolecular polarization between the

phthalocyanine and the metai, the stronger is the rr-interaction between two

phthalocyanines, while coordination to the metai of a second ligand reduces the

magnitude of the x-interaction in metallophthalocyanines and generally leads to

disaggregation [65].

The n-attractions of phthalocyanines are not restricted to self-aggregation, n-stacking

being observed between phthalocyanines and a wide variety of aromatic compounds in

organic solvents [66-671. Metalation with zinc generally enhances the interaction, while

the use of toluene as solvent can dismpt the interaction and open up folded or stacked

conformations [67]. The phthalocyanine metal atom is the site of the shortest

intemolecular contact and the solvent atom closest to the metal is always electron-rich.

According to C. A. Hunter and J. K M. Sanders [68], the optimum interaction of two

phthalocyanines in solution is predicted for the geometry which places the pyrrole ring of

one phthalocyanine directly above the n-cavity at the center of the other (Figure 3). The

geometry illustrated in Figure 3 is in agreement with the experimentally detemiined low-

temperature geometry for the zinc porphyrin-zinc porphyrin interaction in CH,Cl,

solution [68].

These self-aggregation phenornena for porphyrins and phthalocyanines have a strong

effect on the 'H NMR spectra of these compounds. Abraham et al [69] were the first to

investigate the concen?ration dependence of fiee-base coproporphyrin spectra. Later

Janson and Katz [70] extended these investigations to the mesoporphyrin M,

protoporphyrin IX and deuteroporphyrin IX dirnethyl esters. These concentration effects

were attzibuted by Abraham to the self-aggregation of porphyrin molecules in solution

~ 9 1 .

Figure 3: The optimum interaction of two Pcs.

Temperature effects on the chemical &if€, on the other han& are generally smaller for

porphyrins than those of concentration, but still measurable. Over the range -50 to 30 OC,

the inner N-H protons of coproporphyrin III are shifted by 0.27 ppm, whereas shifts for

the other proton species are 0.005 pprn or les. Between 20 and 40 OC, the usual

operathg range for 'H NMR spectrometers, changes in chemical shifts are generally of

the order 0.0 1 -0.02 pprn (0.1 pprn for the N-H protons), and thus are usually ignored.

'H NMR spectra of phthalocyanines are compriseci of three groups of signals. First, two

equivalent N-H protons in the metai fiee phthalocyanine are found substantially upfield

Erom TMS. The chernicd shifts can Vary nom -6 pprn for the binuclear phthalocyanines

to -1 pprn for very soluble phthalocyanines with bulky peripheral groups that can prevent

aggregation. For example, in binuclear phthalocyanine linked by oxygen (79) the N-H

protons are found around -3 pprn [57]. For the binuclear phthalocyanine linked by

catechol70, a N-H proton signal was observed in the region of -6 ppm, when the spectra

are nui on samples at high concentration (IO-' M). When the concentration was decreased

to 10-~ M the N-H proton signal was observed at -3 pprn and remaineci constant upon

fûrther dilution. Furthexmore, at intermediate concentrations (1 0" M), the observation of

two NH signals at -4.1 and -3 .O were noted and explained as the representation of a

mixture of fiee and aggregated phthalocyanines. The effect of temperature on the 'H

NMR of 80 was complicated by the concomitant effect of solvent on the intemal N-H

signal. Thus, in toluene-d,, the chernical &if€ of N-H signal (at 104 M) at 80 OC is -3.0, at

22 O C it is -2.60 and at -80 OC it is -0.9 ppm. On the other hand, in CD,CI,, the N-H

signal is invariant between -70 OC and 22 OC and broadens greatly in CD2C12 at 50 OC

[42]. The benzene soluble, symmetrical, metal-fiee 2,3,9,1O, 16,17,23,24-

octa(hexadecy1)phthdocyanine (109) exhibits an N-H signal at -1.05 pprn (CsDs)- The

less soluble 2,3,9,lO, 1 6,17,23,24scta(1,4,7,1 O-tetraoxaundecy1)phthalocyanine (1 10)

shows a N-H signal at -3.2 pprn [42] (Figure 4). The intemal N-H protons of 1,2% 1 1,15-

bis(2',2'-diocty lpropan-l ',Y-dioxy)p hthaloc yanine (1 1 1) presented a broad signal shi ft ed

upfield to -5.79 pprn at 5x1 O-' M and shifted downfield at lower concentration (5x1 O' M)

[25] (Figure 5). It is very difficult to compare NME2 data among mononuclear

phthdocyanines, because concentrations have not generally been reported in publications.

Less soluble, more aggregative phthalocyanines exhibit N-H signals M e r upfield than

more soluble, less aggregated species. Broadness of the signal is larger for less soluble

phthalocyanines and the reported value is approximate (for exarnple between -3 and -4

ppm) or cannot be observed at all. For more soluble phthalocyanines the N-H absorbame

is M e r downfield and cm be reported exactly.

Figure 4: Illustration to Pc aggregation.

A second group of 'H NMR signals are the arornatic protons of the phthalocyanine benzo

groups. They exhibit chernical shifts at 8 to 10 ppm, which is expected for compounds

with large x-systems. Protons 1 and 4 in substituted metal phthalocyanine absorb at 9.60

pprn and the 2 and 3 protons at 8.27 pprn, M e r upfield and m e r f?om the center of

the phthalocyanine ir-system (This spectral data is analyzed for PcSi[OSi(C6Hl,),],

(1 12)) [71] (Figure 4). Exact values for aromatic protons for phthalocyarilnes can be

reported only for symmeûicai or single isomeric phthdocyanines. For example,

phthalocyanine 109 has a signal for aromatic protons at 9.62 ppm, that is very close to

disaggregated unsubstitutai phthalocyanine 1 12. On the 0 t h hand, the less soluble

phthalocyanuie 110 exhibits an absorbante of aromatic protons at 8.71 ppm, which is 0.9

pprn upfield. That fact c m be explaineci by aggregational phenornena of phthalocyanines.

Phthdocyanines in solution are mobile and the NMR signals seen are £tom a

combination of al1 possible configurations of aggregated phthalocyanines. T'us, for more

aggregated p hthalocy anines, the aromatic pro ton signals are M e r up field than those for

the less aggregated phthalocyanines. The clifference in chemical sh ih between the

aromatic protons of compounds 109 and 110 is 0.9 ppm, smaller than that between the

interna1 N-H protons at - 2.15 pprn [42]. Detailed studies of the NMR spectra of the

aromatic protons of Pc 11 1 show that different aromatic protons are shifted diflerently

[25]. With changing the concentration 10 times, fiom 5x 1 O" M to 5x 1 O4 M, the doublet

signal of proton "c" exhibited the largest change of chemical shifi fiom 7.75 to 8.32 pprn

(0.57 ppm) (Figure 5). The signals of protons "a" and '%" exhibited smailer changes of

the chemical shifts with the same change of concentration. The triplet signal of proton

"b" changed fiom 7.27 to 7.67 pprn (0.40 ppm) and the doublet signal for proton "aY*

moved nom 6.83 to 7.25 pprn (0.42 pprn). This allowed an assignment of the highest

field aromatic doublet signal to the hydrogens at the 4,8,18, and 22 positions and the

tnplet signal to the hydrogens at the 3,9,l7,23 positions of the Pc macrocycle.

nie 1st group of NMR signals for phthdocyanines belong to the peripheral groups and

usually they are not affecteci by aggregation phenoznena M y , if the peripherai group is

very close to the macrocycle ring of the phthaiocyanine c m this change be observed as in

case of phthalocyanine 111 [25]. The side-strap meîhylene (CH3 goup signal was

changed by 0.41 ppm (Figure 5).

Figure 5: 1,11,15,25-tetrasubstituted Pc.

RESEARC'& PLAN

Many new substituted phthalocyanines were synthesized since the discovery of the parent

unsubstituted phthalocyanine in 1907 by Braun and Tcherniac [72]. The interest for these

research studies were inspired by the unique properties of metal and metai fkee Pcs. Novel

applications required distinctive phy sical and chernical properties of Pcs. Substitution of

the benu, groups together with replacement of intemal protons with various metals cm

yield Pcs with properties required for a particular application. Differently substituted

phthalocyanines c m be soluble in water or organic solvents. They can have electron-

withdrawing or electron-donating groups as substituents of the benzo rings. They can be

optically active or exhibit unique W-vis absorption because of their substituents.

For a long tirne, 4-neopentoxyphthdonitnle (8b) was used in our laboratory for the

synthesis of binuclear and unsymmetrical mononuclear phthalocyanines as a starting

material. Phthdonitrile 8b can be easily synthesized nom commercially available Cnitro-

phthdonitde (6b). Phthdocyanines with neopentoxy substituents are readily soluble in

organic solvents and easy to puri@ and characterize. The disadvantage of 8b as a starting

material is that al1 of the Pcs that were made fkom this compound were isolated as a

mixture of inseparable isomers. The NMR spectra of such compounds represent a sum of

signals fiom different isomers and are not very informative. Moreover, recent progress in

the field of PDT of cancer using Pcs required single isomers for medicai research.

Halogenated phthalonitriles are excellent precursors for the synthesis of substituted

phthalocyanines. Unfortunately, the preparation of these compounds requires a difficult

multi-step synthetic procedure. With the exception of monohalogecated phthaloniûiles

and tetrabromophthalonitrile, bromo- and iodo-substituted phthalonitriles are h o w n ,

even though halogenated phthalocyanines are widely used in the dye industry where they

are prepared by direct halogenation of the msubstituted parent phthalocyafunes.

We were interested in exploring the possibiiities of synthesizing of halogenated phthalo-

nitriles using simple procedures. We thought that direct iodination of phthdonitrile (3)

would be impossible. The iodination of aromatic compounds usually employed harsh

acidic condition in which the nitrile groups of phthdonitrile will be hydrolyzed. Although

iodination of phenols cm be easily achieved using iodine nitrite [76], attempts to use the

same conditions with 4hydroxyphthalonitri1e were not very successful[34]. The yields

of iodohydroxyphthalonitn1es were below 10 % even if a hydroxy group was present to

activate the aromatic ring toward electrophilic aromatic substitution. We decided to direct

our attention to phthdimide as the starting material for the synthesis of halogenated

phthalonitriles. In spite of the fact that iodo- and bromo- substituted phthalic acids are

known, we decided not to use these compounds as starting materials. The first step of the

conversion of phthalic acids into the phthalonitriles involved a high temperature pyrolysis

of the ammonium salt of phthalic acid and we had a concem that iodo or bromo

derivatives of phthalic acid will not be stable under such conditions.

Another approach to the synthesis of halogenated phthalonitriles led us to the investi-

gation of the direct bromination of phthdonitrile (3). We supposed that bromophthalo-

nitriles will have properties comparable with iodophthalonitriles toward catalysis by

transition metals in substitution reactions and probably will be more stable to light and

temperature. We were planning to examine several brominating agents and especially the

seldom used Na-dibromoisocyanuric acid (NBI) known to brominate aromatic

compounds containing both activating and deactivating substituents.

As mentioned before, the disubstituted iodo- and bromophthalonitriles were unknown .

Therefore, we decided to pay special attention to the synthesis of these compounds.

Particularly, we were interesteci in developing convenient syntheses of 4,s- and 3,4 - disubstituted phthalonitriles. 4,s-Disubstituted phthalonitdes are starting materials in the

synthesis of 2,3,9,lO, 16,17,23,24-octasubstituted-Pcs. These phthalocyanines can exist

only as single isomers and could be useful in many applications where single isomen of

Pcs are required. On the other hand, 3,4-disubstituted phthalonitriles and l,2,8,9,15,16,-

1 2,23-octasubstituted-Pcs are unknown and the synthesis of 3,4-dihalogenosubstituted

phthalonitriles could open a way for the synthesis of this new group of substituted Pcs.

The second aspect of this project involves the synthesis of mono- and binuclear single

isomer of Pcs using dihalogenated phthalonitriles as starting materials. nie substitution

reaction with 1 -alkynes is well known and was used in our laboratory to synthesize Csub-

stituted monoalkynyl phthalonitriles fiom Ciodophthalonitrile (12b) [35]. We decided to

concentrate our attention on dialkynyl derivatives of phthalonitriles as an example for the

application of the dihalogenated phthdonitriles. We were planning to use single isomer

octaallcynyl phthalocyanines and dodecaakynyl binuclear Pcs for 'H NMR studies. Very

good solubility of these compounds in organic solvents and the simplicity of their 'H

NMR spectra rnake these Pcs excellent candidates for investigation of the dependence of

chemical shifts on concentration and temperature. Moreover, metalated and metal-fiee

alkynyl-substituted phthalocyanines may be valuable as potential candidates for liquid

crystals and other applications where red-shifted and soluble Pcs are needed.

RESULTS AND DISCUSSION.

SYNTHJBIS OF BALOGENATED PHTHALONITRILES

Synthesis of 4,5=düodophthaIonitrüe (1 17a) and 3,4aiiodophthalonitrile (117b).

There are a number of examples in the literature concemhg the halogenation of aromatic

compounds containhg two electron-withdrawing groups ortho to each other [78-821.

Each of these reactions exhibits a different distribution of halogenated isomers. In the

case of the iodination of nitrobenzene [8 11 and the bromination of phthalic anhydride

only the 4,Sisomer was found [78,82] . On the other hand the iodination of phthalic

anhydride led to the 3,4; 4,s; md 3,6-isomers, and this isomer distribution was

temperature dependent [79]. The 3,Ssomer was not isolated fiom any of these reactions.

These facts demonstrate the well known directional effect by the halogens of the ortho

and para positions in the aromatic ring. Although there are not enough data to determine

the quantitative distribution between attacks of the halogen at the 3- or 4- positions at

different temperatures , we can suggest that, by increasing the temperature, we are

increasing the possibilities of electrophilic attack at the 3 position. These obsenrations

show the importance of temperature control in these reactions. The results reponed herein

are also in agreement with these observations. An increase in the temperature of the

iodination of phthdimide l a d s to the production of the 3,4-isomer.

In view of the fact that nitration of phthalimide yields chiefly 4-nitrophthalimide [83]

while nitration of phthalic anhydride gives a mücture of 3- and rlnitrophthaiic acids [84],

the partial, direct ionination of phthalimide might be expected to be a better potential

source of the 4,s-diiodo isomer. Direct iodination of phthalimide (113) in 50% oleum for

six &y s at 90- 1 00 OC, followed by hydrolysis of the produced phthalirnide to the

correspondhg phthalic acid gave 4,s-diiodophthalic acid (114) in 55% yield [84]. The

relative yield of 114 with respect to other products of iodination was 1 1 % in the case of

iodination of phthalic anhydride at 75-80 OC [79]. The 4,5-diiodophthalimide (1 l5a) was

not isolated and was used in situ to produce 114. We believed that milder reaction

conditions, such as decreasing the concentration of fuming sdfuric acid and decreasing

the temperature of the reaction can fùrther increase the relative production of the 4,s-

isomer.

There is only one method available for the iodination of aromatic compounds containhg

electron-withdrawing groups. This method uses iodine in fuming sulfunc acid. A

mechanism for this reaction has been proposed by J. Arotsky et al. [80]. According to

this mechanism the reactive species is either b* or 12+, and temperatures of at least 60 O C

are required for this reaction to proceed.

In the present work the iodination of 113 was carried out in 33% fumuig sulfùric acid at

75-80 OC. The main product was 4,s-diiodophthalimide (115a) and only a trace amount

of 3 ,4 -d i iodopha lde (115b) was produced. Some of the product was lost during the

work-up of the reaction mixture by the hydrolysis of 115a to 114 by aqueous sulfunc

acid. Both the phthalûnide and phthalic acid products were separated by recrystaUization

fiom an acetonelwater mixture. The separation of 115a from 115b was also accomplished

by recrystallization methods. If the temperature of the reaction mixture was increased

above 80 OC, a greater amount of 1 l5b was produced.

I

1 C O H

Scheme 17

The conversion of diiodophthalimide 1 15a to diiodophthalonitde 1 17a was carrieci out in

two steps. First phthalirnide 115a was treated with concentrated aqueous ammonium

hydroxide solution at 40 OC for 12 h o m to give 4,S-diiodophthalamide (1 l6a) in 80%

yield [85]. Higher temperatures were needed to complete the reaction and still a trace

amount of unreacted phthahnide 115a was detected. It was necessary to remove ail of the

phthalimide fiom the reaction mixture to ensure that pure phthalamide 116a could be

obtained for the nea step. After the reaction, a white precipitate was filtered, washed

with cooled water and then with methanol or acetone to remove unreacted 1ISa. The

filtrate was monitored by TLC (CHC13) until d l stamng matend was removed. Pure 116a

waç dried in the oven at 120 OC and then crushed into a powder for use in the next step.

Phthalamide 116a undenvent dehydration with trifluoroacetic anhydride in

dioxane/pyridine and recrystallization fiom ethanol gave pure 11 7a in 79% yield using

the previous work-up procedure 1861. The syntheses of 117a and ll7b are outlined in

Scheme 17.

If 115a was not purified and a mixture of 1158 and 115b was used for the synthesis of

phthalonitriles, both 117b and 117a were present. To separate the 3,4- fÎom the 43-

isomer, the reaction mixture was recrystallized twice fiom ethanol. Pure 117a was

isolated, and the mother liquid was separated using flash chromatography on silica gel

using hexane/ethyl acetate (9/1). The first hct ion yielded 117a, the second fraction

contained a trace of Ciodophthalonitrile (12b) and fiom the third fraction, Ll7b was

isolated in less than 10% yield.

The 'H NMR spectrum of 1 1 7a was very simple. Only one singlet at 8.1 ppm belongs to

two identical protons, but both the 4,s- and 3,bisomers can exhibit the same NMR

pattem. We compared this spectnim with the spectrum of 4-iodophthaionitrile (12b). The

spectrum of 12b has three signals: a singlet at 8.1 pprn belongs to the proton at C,, the

doublet at 7.6 pprn to the proton at C, and the doublet at 8.0 ppm to the proton at C,. We

assurned that we have the 43- isomer because of the chexnical shift, but M e r proof was

needed to identiQ the structure of 117a. Phthalonitrile 11% showed two doublets in its

'H NMR spectnim at 7.6 and 8.1 ppm assigneci to the protons at C, and C, respectively.

Electrophilic bromination of phthalonitrile (3).

Electrophilic bromùiation of aromatic compounds containhg electron-withdrawing

groups is dificuit and commody involves high temperature and strong acidic conditions.

The number of reagents capable of brominating strongly deactivated aromatic substrates

is very limited. For example, different conditions for the bromination of nitrobemene are

presented in Table 1 [86-881.

Table 1 : The bromination of nitrobenzene (1 18) to 3-bromonitrobenzene (119).

~eact ion

Medium

NBS, H2S04

Temperature

1.5 hours

5 minutes

Percentage

Yield

3-Bromonitrobenzene (119) can be synthesized fiom nitrobenzene (1 18) by treatment

with brornine at 120 OC for 1.5 hours in the presence of Fe [Ml. An alternative method to

prepare 119 is to treat this compound with N-bromosuccinimide (NBS) in sdfunc acid at

85 OC for 3 hours [87]. Other conditions for the synthesis of 119 fiom 118 involves the

brominating reagent N,N-dibromoisocyanuric acid @BI) (120) in concentrated sulfunc

acid [88]. Al1 three reactions produced compound 119 in high yields, but for completion

of the bromination in the first two reactions, high ternperatures were necessary. The use

of 120 in sulfuric acid produced similar results but required a shorter reaction tirne and

lower ternperatures.

Furthermore, experiments utilking 120 in 15% oleum were used for the one step

perbromination of O- and m-dinitrobemenes [88,89]. The results from these experiments

are outlined in Table 2. It was found that a hi& yield of the monobrominated

Table 2: The bromination of aromatic compounds with two electron-witbdrawing groups

with DBI (120).

Reaction

T h e

15

minutes

1 minute

15

minutes

- -- - -

. / O [ Product 1 References

Yield

dinitro benzene

5% Tetrabromo-m-

dinitro benzene

89% Tetrabromo- [891

phthalic acid

species was produced when m-dinitrobenzene was used as a substrate. Reaction of m-

dinitrobemene with 120 in 15% oleum for a prolonged reaction time produced

tetrabromo-m-dinitrobenzene but with a very Iow percentage yield. Conversely, in the

case of O-dinitrobemene where a relatively short reaction time was used, a high

percentage of tetrabromos-dinitrobenzene was produced. Bromination of phthalic acid

(Sb) in 15% oleurn for 15 minutes led to tetrabromophthalic acid in 89 % yield and it

took a 1 hour reaction in concentrated suifbric acid to completely brominate p-

nitrotoluene 130 to produce tetrabromo-p-nitrotoluene in 93% yield.

Phthdonitrile (3) contains two deactivating electron-withdrawing nitrile groups which are

susceptible to hydrolysis under acidic conditions. Thus, based on the findings outlined in

Tables 1 and 2, it was thought that ody 120 in the presence of concentnited or fùming

sulfunc acid could be successfd in the direct bromination of 3 while minimizing the

exposure of the two nitrile groups to the harsh acidic conditions required for this reaction.

Compound 120 was prepared using the procedure of Gottardi [88] and its synthesis is

outlined in Scheme 18.

Scheme 18

Compound 120 contains 2 reactive bromine groups per molecule and is proposed to be a

source of a positive bromonium ion. Lambert et al. [87] have illustrated that the actual

halogenating rnoiety is not fiee halogen since the bromination of benzene with Brz in the

presence of sulfuric acid resulted in a very srnail amount of product (2%) king produced.

A more recent report by Konradsson et al. [go] on the successful application of N-

iodosuccinirnude (NE) in trifiuoromethanesulfonic acid (CF3S03H) for the generation of

the iodonium ion, suggests that the protomtion of NIS with strong acids, such as sulfi.uk

acid, could generate a positive haloniun species capable of halogenating aromatic

compounds. Andnevskii et al. [91] have reported studies whereby the brominated cation

generated in the bromination of deactivated aromatic compounds is stabilized in the

sulfunc acid medium as a resdt of bonding with the HS04' counter ion. Therefore, these

combined studies suggest that the brominating agent 120 is a source of the protonated

positive species which is stabilized in a similar manner.

In an attempt to directly brominate phthalonhile (3), 120 was dissolved in 30% fumiog

sulfuric acid in an ice bath and dlowed to react with 3 for 30 minutes in a 1 :2 ratio. The

obtained crude mixture contained a mixture of unreacted 3, monobrominated (13, 12 l),

dibrominated (122,123,124), tribrominated (125,126) and tetrabrominated (127)

phthalonitriles. The reaction mixture was separated by flash chromatography on silica gel

using a gradient of ethyl acetate - hexane as eluent. Separation by this method proved to

be very difficult and tedious due to the fact that the compounds had very close retention

times. Smail hctions were collected and separation was monitored using thin layer

chromatography (TLC). Most of the fiactions contained a mixture of products and had to

be rechromatographed using similar conditions. Partial recrydIization was involved in

this separation because some of the compounds were much less soluble than others. The

compounds obtained were characterized by elementai analysis, 'H NMR and mass

spectroscopy (MS).

nie 'H NMR spectrum of the second fiaction obtained contains a single peak at 8.2 ppm

and it was thought to correspond to the single hydrogen of 3,4,5-tribromophthalonitriie

(126). The results of the 'H NMR led to the belief that this k t i o n contained 126 as a

pure compound. However, the MS of the same fiaction exhibits a peak at m/z 444 with a

pattern typical for tetrabromo compounds (ndz 440,442,444,446,448 with relative

intensities of 1 :3:4:3: 1) indicating that 3,4,5,6-tetrabromophthalonitrile (127) was also

present in this hction. A peak corresponding to the molecular ion of compound 126 was

also found (dz 362,364,366,368 with a relative intensity of 1 :2:2: 1). This mixture of

compounds was inseparable and had a sharp melting point at 180-1 8 1 OC.

'H NMR and MS spectroscopy were also used to distinguish which of the

dibromophthalonitriles were present in the various hctions. The hct ion that contained

pure 3,4-dibromophthalonitriIe (123) was identified by the presence of two doublets at

7.8 and 8.0 ppm, respectively. Both 3,6-dibromophthalonitde (122) and 4,s-

dibromophthalonitrile (124) are syrnrnetncal and contain two hydrogens which are

chemically equivalent and thus, both display a single singlet in their respective 'H NMR

spectra. In the case of 124, the hydrogens are adjacent to two electron-withdrawing

groups (nitrile and bromine) while in the case of 122 they are only adjacent to one

bromine group. As a resdt of this, the singlet correspondhg to the hydrogens of 124

appeared more downfield than that correspondhg to 122. Thus, the compound 124

displayed a singlet at 8.0 ppm while compound 122 displayed a singlet at 7.7 ppm.

Isolation of compounds 122 and 123 indicated to us that both 3-bromophthalonitrile (121)

and Cbromophthalonitrile (13) are formed dining the brornination reactions. However, at

first, only 13 was isolated as a pure compound. The 'H NMR spectnim of 13 contained

three signals: a singlet at 8.1 ppm with a small splitting ftom the meta coupling with the

proton at Cp, doublets at 7.9 ppm (proton at Cg) and at 7.7 ppm with a smdl splitthg

fiom meta coupling with the C3 proton which corresponded to the proton at Cs of 4-

bromophthalonitrile (13). Thus the data c o h the evidence of the correct previous

assignment of compounds 121 and 124. The isolation of 121 was much more dificuit,

because of the similarity of its retention tirne with that of the starting matenal 3. We

could see the NMR pattern of 121 in the mixture of 3 and 121 in the last hction, but

without NMR data of pure 121 we couldn't prove that this compound was present in the

reaction mixture. Cornpound 121 was thus synthesized independently nom 3-

nitrophthdonitrile (6a). The synthesis and physical properties of 121 will be descnbed

later. With the 'H NMR spectrum of a pure sample of 3-bromophthalonitrile (121) we

could establish the exact retention tirne of 121 and separate it fkom the starting material 3.

Relative retention times of the products of bromination of phthdonitrile (3) are presented

in Table 3.

Table 3. Rf of products of bromimtion of phthaionitrile (3) with DBI (120). TLC silica

gel plates (Kodak), eluting mixture ethyl acetate: hexane (1 :4).

124 0.56

126 and 127 0.70 d

Because of the difficulties experienced in separating the reaction products by flash

column chromatography and in order to estabiish optimum conditions and pathways of

reaction, High Performance Liquid C hromatograp hy (HPLC) was used for monitoring the

bromination reaction. The reaction was repeated in sulfunc acid with varying

concentrations of sulfur trioxide and the reaction times between 1 minute to 2 hours. The

retention times of the various monobrominated and dibrorninated phthdonitriles were

deduced fiom the resuits obtained when compounds 3 and 121- 127 were individually

analyzed by HPLC. A Supel Cosil LC8 column (length 250 mm, diameter, 5 prn particle

size) was used for this separation. The retention times observed ere presented in Table 4.

Table 4. Retention times of products of bromination of phthalonitrile (3) with DBI (120).

HPLC column Supel Cosil LC8, eluting system methmol : water. (Ratio Water: Methanol

(60:40, 10 min, 50:50,20 min, 40:60, 10 min, 0:100), Flow rate 0.5 mL/min, Wavelength

of UV detector 250 nm)

125 and 126

The retention time of 3 itself could not be deterxnined when this individual compoimd

was injected into HPLC system. This wuld be attributed to the fact that pure

phthalonitrile is very insoluble in these solvents. As a result of this observation, a knom

concentration of 3 in the presence of a mixture of bromo substituted phthalonitriles was

analyzed by HPLC. Cornparison of the two chrornatograms reveded that when the

concentration of 3 was doubled, the intensity of the peak produced at 9.54 minutes also

doubled. Thus, 3 was identified to have a retention time of 9.54 minutes. Its insolubility

was demonstrated even in the presence of a mixture by the fact that the peak produced at

9.54 minutes contained a shoulder. From Table 4, it was observed that compounds 122

and 124 have retention times of 20.74 and 20.64 minutes respectively, when individually

injected into the HPLC column. However, as a result of the similarity between the two

individual retention times, in the reaction mixture, both 122 and 124 were eluted together

with a retention time of 20.84 minutes. Fortunately, the retention times of those

compounds on flash column chromatography on silica gel or on TLC were different

(Table 3). Both HPLC and column chromatography had to be used for the determination

of the percentage yields of compounds 122 and 124. The HPLC chromatogram for

compounds 126 and 127 revealed two peaks which had retention times of 30.07 and

3 1 .O4 minutes, respectively. From the retention times of the other brominated

phthalonitriles obtained, one observes that the îollowing pattern has been established.

Unsubstituted phthalonitrile 3 elutes &st with the lowest retention thne followed by the

monobrominated phthalonitriles followed by the dibrominated phthalonitriles. Thus, fiom

these observations, one c m make the assumption that the peak at 30.07 minutes

corresponds to tribromophthalonitrile 126 (and possibly 125) and the peak at 3 1.40

minutes corresponds to tetrabromophthalonitrile 127.

The percentage of each compound that is present in the crude mixhae, obtained fiom the

various reactions, was calculated by sethg up standards which consisted of a mixtlne of

the various brominated phthalonitriles of known concentrations. The amount of the

respective substances present in the known concentration of each HPLC sample was

calculated based on the peak height ratio of the compounds to the standard. This in tum

was used to calculate the amount of each product present in the crude mixture. By

comparing the amount of each compound produced in the crude mixture with the amount

of 3 used as starting material, yields were obtained.

The calculated yields of the various phthalonitriles produced in the different reaction of 3

with 120 in 30% fuming sulfuric acid are outhed in Table 5.

It is expected that, with longer reaction times, a greater amount of starting matenal should

be consumed. The data in Table 5 illutrates that the amount of starting material present

in the reaction mixture decreased with t h e . We did not report the concentration of the

starting material in the 1 minute reaction, because of poor solubility of 3 in the rnethanol :

water mixture.

Table S. The calcuiated isolation yields of the products of reaction of 3 with 120 in 30%

fuming sulfunc acid at different times (niinutes).

:ombined yield

Zombined Conversions

The yields of monobromophthalonitri1es 121 and 13 increased between 1 and 15 minutes

and then started to decrease over time. The graduai decreasing amount of these products

observed over time may be attributed to the fm that these products undergo subsequent

bromination or decomposition as a result of prolonged exposure to the harsh acidic

conditions. With respect to each other, the two monobrominated substances were

produced in approximately equal amounts. Thus, fkom the resuits obtained, one can

conclude thaf under these conditions, the optimum reaction tirne which yields the greater

amount of monobromophthaionitdes lies close to 15 minutes.

The dibrominated phthalonitriles 122 - 124 show a different pattern of formation than that

which was observed for the monobrominated phthalonitriles. It was found that the

amount of dibrominated products increases between 1 and 20 minutes and then starts to

decrease as a result of m e r bromination and decomposition. Similarly to the

monobrominated phthalonitriles, the amount of dibromophthalonitriles produced with

respect to each other under these reaction conditions was virtuaily equai.

Similar calculations were performed to detemiine the amount of the

tribromophthaionitdes 125 and 126 and tetrabromophthalonitnle 127 obtained in the

crude mixtures of the various reactions, respectively. These results are also presented in

Table 5 and they are similar to those obtained for the dibrominated compounds for which

the amounts of 125,126 and 127 increased between 1 and 20 minutes and then started to

decrease. The decrease in yields observed at longer reaction times may aiso be

due to decomposition of the products. Compound 127 appears only to be formed in trace

amounts throughout the various &on times while 125 and 126 was present, in the

optimum reaction t h e of 30 minutes, in a greater yield that which was observed for the

di brorninated products .

Figure 6. The Mass Spectrum for 1 min reaction of 3 with 120.

A mass spectrum of both the shortest and longest reaction times of 3 with 120 in 30%

fuming sulfùric acid was taken. A spectnun for the 1 minute reaction is illustrated in

Figure 6. Each spectrum shows a peak at ml. 444 revealing that 127 was present in the

crude mixtures. In addition, the peak at m/z 463 likely represents a decomposition product

of 127 whereby one of the cyano groups has been replaced by a carboxyl group. Tnus, the

presence of this compound connmis that even after 1 minute, the various phthalonitriles

produced partially hydrolyze to carboxylic acids under the acidic conditions of the

reaction. Trace amounts of pentabromocyanobeazene and hexabromobenzene were found

in the MS spectrum of the reaction mixture with the longest reaction tirne. It is interesting

that the bromination reaction does not stop upon formation of tetrabromophthalic acid or

tetrabromocarboxycyanobenzene. It is possible that decarboxylation and subsequent

bromination cm occur under these reaction conditions.

In an attempt to improve the yields of the products produced and slow down the

decomposition, the reactions of 3 with 120 were carried out utilizing concentrated

suifûric acid as the solvent at various reaction times. The crude mixtures obtained fiom

these reactions were analyzed by HPLC in the same way as those conducted infimirtg

sulfûric acid. The results kom these reactions are summarized in Table 6.

Initially, 3 reacted afier 120 minutes with 120 in concentrated sulfunc acid with different

ratios of phthalonitrile (3) and DBI (120) (2: 1- one mole of 3 to one mole of reactive

bromine atom, 1.5: 1 and 1 : 1 - one mole of 3 to two mole of reactive bromine atom) to

give, in addition to the starting material, monobromophthalonitriles 121, 13 and

dibromophthalonieiles 122 - 124. It was observed that although most of 3 was consumed,

the calculated yield of 121 was only slightly better than the one obtained fiom the

reaction conducted in 30% fuming sulfunc acid, but the yield of 13 was much higher. The

dibromophthalonitriles and tribromophthaloniûiles were obtahed in trace amounts and

no 127 was observed to be produced under these reaction conditions. It appears that the

decomposition rate increases with increasing concentrations of 120 and although, the

yields of monobromophthaloniûiles rose with increasing concentration of DBI (120), the

concentration of starting material decreased, probably as a result of decornposition.

Table 6. The yields of the products produced by various reactions of 3 with 120 (1 : 1

ratio) in concentrated sulfùric acid at different times (minutes).

Combined yield

1 Combined conversion

a) Ratio of 3:I2O is 151 .

b) Ratio of 3:l2O is 2: 1

Subsequentiy, the reaction t h e was decreased to 60 minutes. The main products

produced were the monobrominated phthdonitriles with 13 king the predominant

product. Electrophilic attack at carbon four of phthalonitrile (3) cannot be explained by

the deactivation eEects of two cyano groups. Position 3 is ortho to one nitde group, but

is meta to the other. Position 4 is in meta orientation to one cyano group and in para to the

other. A possible m o n why the formation of 13 is favored over 121 could be due to

steric effects. In the case of 13, the bromine group is not adjacent to any substituents and

thus, is less stericaily hindered than in the case of 121.

The same reaction carried out for a period of 30 minutes did not produce results that were

significantly different fiom those that were observed fiom the 60 minute reaction. Further

decreases of the reaction time to 20 and 10 minutes slightly affected the yields of the

main product. These results are a combination of bromination and decomposition

reactions and the optimum reaction thne for the bromination of 13 in concentrated

sulfunc acid is 30 minutes. This is a very good method for the one step synthesis of 13

using phthalonitrile (3) as starting material, but for the synthesis of

dibromophthalonitriles we decided to try 8% fuming sulfuric acid as the solvent. The

results fiom these reactions are summarized in Table 7.

We decided to investigate only two bromination reactions with reaction times of 10 and

20 minutes. nie yields of the dibromophthalonitriles were slightly increased with

increasing reaction times. Increasing the reaction time also produced more decomposition

Table 7. The calculated isolation yields of the pmducts of reaction

of 3 with 120 in 8% fuming sulfunc acid.

Yield %

Time (min)

L Isolated yield (Colurnn cbromatography on silica gel)

1 O'

Combined yield for 3 and 121.

Combined yield for 125 and 127.

products and we therefore decided to stop the reaction after 20 minutes. The reaction

mixture was poured ont0 ice and extracted with diethyl ether. The organic layer was

separated and washed three tirnes with 2% sodium bicarbonate, sodium thiosulphate,

water and dried with MgS04. The ether was evaporated and the residue was separated on

flash silica gel column ushg hexane/ethyl acetate as an eluent. The isolated yields are

listed in the Table 7. The lower isolated yields of the dibromophthalonitriles in

cornparison to yields determined by HPLC are due to the difficulty in separation of these

compounds, particulady 3,edibromophthalonitrile (123). Al1 of the

dibromophthalonitriles were isolated and characterized for the fï.rst t h e and compound

123 is the first example of any 3,edisubstituted phthdonitrile.

Table 8. The calculated HPLC yields of the compounds produced in the feaction of

brominated phthdonitriles with 120 in 30% fuming sulfunc acid.

Compound produced (yields)

In order to d e t e d e a pathway of substitution that 3 follows as a result of bromination,

the pure compounds isolated by column chromatography were used as substrates for

M e r brornination with 120 in 30% fuming sulfunc acid. Compounds 13,121,122,123

and 124 were used as substrates in the reaction of brornination. ui order to minimize the

amount of decomposition products produced, we decided to use the reaction time of 5

minutes. Conveaely, monobromophthalonitriles 121 and 13 were left to react for 30

minutes since periodic TLC analysis on the respective reactions indicated that rnost of the

substrate was consumed after only 30 minutes. The reaction products and their respective

yields within the cmde mixtures were determined by using the HPLC method described

previously and are summarized in Table 8.

The resdts obtained indicate that all three of the dibromophthalonitriles produced were

capable of undergoing m e r bromination. It appears that 4,5dibromophthaionitrle (124)

was the most reactive among of the three dibrominated phthalonitriles generating 126

which was subsequently brominated to yield 127. The results obtained fkom the reaction

where 122 was used as a substrate indicate that, in addition to the starting material, both

tribrominated and tetrabrominated phthalonitriles were produced. Arnong the two

tribrominated phthdonitrile isomers that can possibly be produced (3,4,5-

tribromophthalonitrile (126) or 3,4,6-tribromophthdonitrile (125)), 3,6-

dibromophthalonitrile (122) can only go on to form 125. Since, in the HPLC

chromatogram, a peak was observed at the retention time corresponding to 126, it was

assumed that the two tribrorninated isomers were eluted with the same retention time.

Thus, it appears that the calculated yields of 126 as was determined by HPLC analysis for

al1 the reactions between 3 and 120, may actually represent a combined yield of 125 and

126. However, this assumption could not be confhed due to the fact that compounds

125 and 126 were not isolated fiom any of the fiactions collected fkom column

chromatography .

Similarly to the miction where 121 was used as a substrate, the reaction of 122 with 120

in 30% fimiing sulfunc acid produced tribrominated and tetrabrominated phthdonitdes

in addition to the starting material. However, in the case of 3,edibromophthaioni~e

(123), both 125 and 126 c m be produced, and thus the caiculated yield is likely to

correspond to both tribrominated isomers. The mass spectra obtained fiom the crude

mixture of these various reactions illustrate that 127 was present in al1 of these reaction

mixtures, in addition to some decomposition products.

The results obtained when the monobrominated phthalonhiles were used as substrates

are outlined in Table 8 and illustrate that 121 was more reactive than 13. Compound 121

undenvent bromination to produce 122 and 123, with 122 being produced in higher

yields. Compound 13 on the other hand, underwent bromination to produce 123 and 124,

with 124 being the predorninant product. As was previously illustrated, the dibrominated

phthalonitriles produced fiom these reactions were then subsequently brominated to form

both 125 and 126. Although 127 was not detected in either of the two HPLC

chromatograms, the mass spectra of these two reactions indicate that in addition to some

decomposition product, 127 was indeed present.

The collective results obtained when both the dibrominated and monobrorninated

phthalonitriles were reacted with dibromoisocy anUnc acid (1 20) in 3 0% oleum suggest

that the substitution pathway which phthalonilrile (3) undergoes as a result of

bromination is the one which is outlined in Scheme 19.

The method of direct bromination of phthalonitrile described above is an alternative to

multi-step synthesis of brominated phthalonitriles. Only two bromo substituted

phthalonitriles are descnbed in the fiterature: Cbromophthalonitrile (13) [33] and 3,4,5,6-

tetrabromophthalonitrile (127) [93]. For example, as mentioned in the introduction partof

this-thesis, 13 can be also synthesized fiom 4nitrophthalonitrile (6b). This synthesis

includes 3 steps and affords phthalonitriie 13 in less than 20% overail yield. We were

able to isolate 13 in 45 % yield fiom our reaction mixture. We had some dficulties in the

isolation of 3-bromophthaloniûiie (121) fiom the reaction mixture because of the

similarity of the retention time of 121 and starting material 3. Attempts to use recrystal-

lization methods were unsuccessful because, in al1 of the solvent systems tried, phthalo-

nitrile (3) crystallized first as the much Iess soluble compound and this method can be

used only for removing the bulk of starting material 3 fiom the mixture. On other hand,

compounds 121 and 3 were successfully separated by HPLC and if preparative HPLC is

available, ow direct bromination will be a fast and easy method of synthesis of 121.

Dibromophthalonitriles 122,123 and 124 were synthesized for the first tirne. Although

these compounds were produced in yields below 10 %, for the 3,6- and 3,4-

dibrornophthalontriles (122 and 123), it is the only available method for the* synthesis. It

is a specially important for phthdonitrile 123 because it is the first 3,4-denvative of

phthalonitrile that was synthesized. Many 3,6-derivatives of phthdonitrile are known

[53], but the use of

127 Scheme 19

122 as the starting matenal in substitution reactions c m provide a much wider variety of

3,6-disubstituted phthalonitdes. Because of the importance of the 4,5disubstituted

phthdonitriles in our laboratos, at the present time, we decided to look for a better

synthesis of 4.5-dibromophthalonitrile (124) that can afford a better yield. It is significant

for large scale synthesis when tens of grams of starting matenal are needed. The large

scde synthesis of 124 will be described later in this chapter.

Synthesis of 3-bromophthalonitrile (121).

As a result of the inability to separate phthdonitrile (3) fÏom 121 using flash column

chromatography, compound 121 was synthesized as outlined in Scheme 20.3-

Aminophthalonitrile (1 la) was produced by the catalytic hydrogenation of 3-

nitrophthalonitnle (6a) [34]. The desired compound was isolated by silica gel column

chrornatography and recrystallized nom benzene. Bromophthalonitrile 121 was

synthesized b y the conventional Sandmeyer reaction. This procedure invo lved a

conversion of 1 fa to its diazonium salt and the addition of this salt to a cold solution of

cuprous bromide. The preparation of the cuprous bromide solution involved the addition

of a solution of copper sulfate and sodium bromide to a solution of sodium metabisulfite

and sodium hydroxide [92]. The crude product of the Sandmeyer reaction was purifieci by

silica gel column chrornatography and recrystallized fkom benzenehexane to give 121 in

45% yield. The 'H NMR spectrum of 121 consists of three signals. The doublet at 7.9

ppm corresponds to the hydrogen at the 6 position, because of the effect of the adjacent

cyano group. The doublet at 7.8 ppm corresponds to the hydrogen at the 4 position and

the triplet at 7.6 ppm belongs to the hydrogen at the 5 position. The mass spectnim of

compound 121 shows the mo1ecuIa.r ion as a doublet with equal intensities, consistent

with the isotopic ratios for bromine containing molecules.

Scheme 20

Synthesis of 4,s-dibromophthalonitrile (124).

The successfid synthesis of 4,5-diiodophthdonitrile (1 l7a) nom phthdimide (1 13) gave

us an idea to try to prepare 124 using the same route. The treatment of phthalic anhydride

with two equivalents of bromine leads to a mixture, as would be anticipated. The

principal product is said to be the 4,s-dibromophthalic anhydride [81], but in one instance

[78] it is recorded that only 3,4-dibromophthalic acid was secured. The method of

bromination is outlined in the literature [81]. We decided to use 33% instead of 60%

fuming sulfuric acid and reduce the temperature of the reaction to 60 OC. A srnail amount

of iodine was used as a catalyçt for the bromination reaction. We were able to isolate only

two products of the reaction; 4,5dibrornophthalimide (128a) and 4,5dibrornophthalic

acid (128b) the product of hydrolysis of 128a. No 3,4-isomer was found, as in the case of

iodination of phthalimide.

The conversion of lZ8a to 124 was camied out in two steps. First phthalamide 130 was

synthesized by treatment of phthalimide 128a with concentrated aqueous ammonium

hydroxide solution at 40 OC. The reaction t h e was shorter than for the 4,s-

diiodophthalimide (1 15a) and no decornposition products were observed. Diiodo

compounds were not very resistant to light and some iodine and yellow decomposition

products could be observed in the solution of these compounds after some exposure to

light . Phthalamide 129 was dehydrated with tri fluoroacetic anhydride in dioxandp ylidine

and recrystallized fiom ethanol to give pure 124 in 85% yield using a known procedure

1851. The synthesis of 124 fiom 113 is outlined in Scheme 21.

The advantages of using 124 instead of 117a for future syntheses are its decreased light

sensitivity and less facile degree of debromination in cornparison with deiodination in

reactions catalyzed by transition metals . The reactivities of 124 and 117a are very close

in coupling reactions.

Scheme 2 1

Bromination of substituted phthalonitriles.

Our interest in phthalocyanine synthesis led us to attempts to prepare a number of

multiply substituted phthdonitriles. The successful direct bromination of unsubstituted

phthdonitrile (3) suggested to us to use the same conditions for the bromination of

substituted phthdonitriles. Multi-substituted phthdonitriles can be used for the synthesis

of bisphthalonitnles and rnulti-substituted phthalocyanines when the presence of electron-

donating or electron-withdrawing groups must be combined with high solubilities of Pcs.

First, we tried the most challenging synthesis. Our attempts to brominate 3- and 4-

nitrophthdonitriles (6a and 6b) were unsuccessful. Two electron-withdrawing cyano and

one nitro groups make the aromatic ring too passive toward electrophilic substitution

reactions even with DBI.

Next, our target was the commercially available 4-tert-butylphthalonitnle (16d). Direct

bromination of 16d was conducteci using the same conditions as for the unsubstituted

phthdonitrile (3). The reaction mixture was treated as descnbed previously and flash

c o l u . chromatography was used to separate the brominated 4-tert-butylphthalonitriles.

The analysis of fiactions by NMR and MS spectroscopy suggested that al1 possible

mono, di and tri bromo-4-ten-butylphthaionitriles were present in the reaction mixture.

Unfominately, the retention times of these compounds were very close and the separation

of the products was too difficult to achieve. We decided to search for another starting

materid for the bromination reaction.

For the next attempt, we chose 4-hydroxyphthalonitrile (7b) [97]. We suggested that the

activation effect of the hydroxy group would not only help the electrophilic substitution

reaction but would reduce the number of possible products of the reaction. We were

expecting that the ortho directing effect of the hydroxy group wili be more important for

electrophilic bromination than the deactivation effect of the two nitrile groups. Moreover,

the hydroxy group c m be readily convertecl into a number of alkoxy, benzyloxy and

phenoxy substituents. This will make bromo4hydroxyphthalonitriles an important

precursor for the m e r synthesis of phthalocyanines.

Compound 7b was synthesized fkom 4-nitrophthalonitrile (6b) using a potassium

carbonate and potassium nitrite mixture in DMSO [34]. Treabnent of 7b with DBI in

concentrated sulfunc acid for 10 min at room temperature yielded 3,s-dibromo4

hydroxyphthalonitrile (13Oa) and a mixture of monobromo4hydroxyphthalonitri1es

consisting of 4-bromo-5-hydroxyphthalonitrile (130b) and 3-bromo-4-

hydroxyphthalonitrile (130c) in 72% yield that was inseparable by flash chromatography.

Chromatography of the product mixture 130b and 130c proved to be quite tedious.

Hence the mixture of 130b and 130c was alkylated using K2C03 and 1-bromobutane to

give 4-bromo-5-butoxyphthaloniûile (13la) and 3-bromo-4-butoxyphthaloniûile (131b)

in 30 and 34% overall yield fiom 7b, respectively (Scheme 22).

130a R= Br, R'= Br 130b R=Br, R' = H 130c R= H, R' = Br

Scheme 22

SYNTHESIS OF DlALKYNYL PHTEFALONITRILES AND OCTAALKYNYL

PElTHAL4OCYGNINES.

Syiithesis 4,54ialkynylphthalonitriles, 2,3,9,10,16,17,23,24-

octaalkynylphthalocyanines and 4,S-ciialkyIphthalonitriles.

Syntheses of monoalkynylphthalonitriles fiom 4-iodophthalonitrile (12b) were developed

in our laboratory [35,4 11. T e ~ y l p h t h a i o c y a n i n e s synthesized fiom these

phthalonitnles were soluble in organic solvents and exhibited red shifts in their electronic

spectra. We decided that the formation of dialkynyl phthaionitriles would be a good

example of the possible application of dihalophthalonitriles and have potential

applications in non-linear optics [53] and photodynamic therapy of cancer [16- 191.

Phthalonitriles 132-135 and the correspondhg phthdocyanines 137-140 were synthesized

in cooperation with K. NoIan.

Three coupling methods were used to prepare the 4 ,5d i~y lph tha Ion i t r i l e s (132-136).

The fvst method was a hi& temperature method involving Pd(PPh3)2C12 in triethylarnine

(TEA) in the presence of a large excess of a temiinal m e with 4,s-diiodophthdonitnIe

(1178) [94]. This method was developed by K. Nolan and can be successfully used only

for terminal alkynes with high boiling points. The by-product of this reaction is a product

of self-condensation of the alkynes. The desired 4,5-diakynylphthalonitnles 132-135

were prepared in 65-90% yields by this method. For the terminal -es which had a

boiling point below 50 OC, alternative coupling methods were employed at room

temperature. One method Uivolved Pd(PPh3hC12 and Cu1 in

Schexne 23

T ' A [95]. hother iow temperature synthesis of 4,s-dialkynylphthalonieiles includes

two steps. Firstly, reaction of the terminal allqme with n-butyl lithium and secondly by

reaction with zinc chioride. The second step is the couplhg of the intermediate zinc

aromatic compound with 117a or 4,5-dibromophthalonitnle 124 in the presence of

Pd(PPh3)2C12 as catalyst [96]. Both methods gave us the desired dialkynylphthalonitriles

in 80-90% yields (Scheme 23).

AU of these allqnyiphthalonieiles are soluble in most organic solvents and could be

recrystallized fiom hexane. The catalytic hydrogenation of some of these compounds

affords 4,5-dialkylphthdonitnles (142-143) (Scheme 23). AIthough diallcylphthalonitriles

can be synthesized using alternative ways [43-461, we think that our synthetic route is

easy and the desired compounds could be synthesized in higher yield.

Many octa~lphthalocyanines are known [43-461. Therefore, we were interested in the

synthesis of octaallcynylphthalocyanines. Al1 of the above 4,5-diallcynylphthdonitriles

were converted to their respective Pcs (137-141) using lithium 1-pentoxidell -pentanol at

1 10 OC. The yields for these Pcs ranged between 30 and 45%. Ail of the phthdocyanines

were soluble in organic solvents such as benzene, toluene, nitrobenzene, THF, CHCI,,

and Pcs 137 and 141 were even soluble in hexane. A representative electronic specûum

for these Pcs is shown in Figure 7. AU of the Pcs have a km= (Qy) at 732 nm. Each triple

bond appears to cause a red shifi in the Q-band region of the Pc of about 4-5 nm at 700

m.

Unexpectedly, we experienced problems in the conversion of these metai fiee

phthalocyanines into zinc Pcs. The usuai procedure using Zn(0Ach in DMF at 120 OC

was unsuccessful, probably due to decomposition of the Pc in these conditions. Direct

synthesis of metal Pcs using DBU/l-butanol with Z~(OAC)~ was unsuccessfid too. At this

point it was suggested by K. Nolan

Figure 7: Electronic spectnim for Pc 141.

that conversion of Li2Pc into ZnPc can be accomplished at lower temperatures. The

ration mixture with PcR8Li2 in bpentanol was cooled to 60 O C and &(OAch was

added to yield the desired PcRgZn 144-148 in 3 0 4 % yields. The ZnPcs were Iess

soluble than their respective metal-fke Pcs, but they were still soluble in most organic

solvents. The typicai electronic spectnim for these Pc is shown in Figure 8. The M, (Qy)

of these Pcs is 714 nm (in chloroform).

Figure 8: Electronic spectnim for Pc 148.

Although the identity of 4,s-diiodophthalonitrile (117a) is M y based on NMR

chernical shift data, the synthesis of 149 would be a more direct proof of the structure of

117a. When 117a was coupled as before, but in a TEiVDMF (1 : 1 ) mixture, with only 2

equivalents of 1 -octyne, a mixture of 4,5-di(l -octynyl)phthalonitriIe (1 32) and the

monocoupled product 4-iodo-541 -octynyI)phthaloaiûile (149) was produced in 40 and 30

% yields, respectively (Scheme 24). Cornpomd 149 exhibited two different singlets in its

'H NMR spectrum which clearly corroborates the fact that 117a could not be 3,6-

diiodophthalonitrile, whose monocoupled product would yield two different doublets.

Scheme 24

Synthesis of 3,4-di(3 J-dimethyl-1-butyny1)phthaioniIe (150) and

lJ,8,9,15,l6J2 J 3 - o c t a ( 3 , 3 - d i m e t h y l - l - b u t y e (153).

Mer we developed methods for the synthesis of 3,4-diiodophthalonitrile (117b) and 3,4-

dibromophthalonitnle (123) it was logical to attempt the synthesis of the correspondhg

dialkynylphthalonitri1e. Because the 3,edihalophthalonitriles are less available than 43-

substituîed isomers, we decided to direct our attention towards the synthesis of only one

3,4-dialkynylphthalonitri1e 150, as the most soluble of ail the di~ylphthalonitri les.

Furthemore, molecdar modehg of the desired Pc showed us that formation of only one

of the four isomers is possible because two triple bonds cannot be pointed in the çame

direction. Therefore, this Pc wiU be an excellent candidate for our NMR studies.

First, 117b was converted into 3,4-di(3,3-dimethyl-l-butynyl)phthalonitriIe (150).

Because of the low boiling point of 3,3-dimethyl-1-butyne we used the room temperature

synthesis (Cd, Pd(PPh3)2C12 in TEA). The two halogens in 3,4-dihalogenophthalonitriles

are not equivalent as in 4,5-dihalophthalonitriles. The iodo or bromo group in the 4

position is more accessible than the halo group in the 3 position. This fact becomes

important for substitution of the second group. When 4-(3,3-dimethyl- 1 -butynyl)-3-

iodophthalonitrile (151) was formed in the first step of the substitution reaction, steric

hindrance prevented the reaction fiom going to completion. An increase in the reaction

t h e led to a deiodination reaction and 4-(3,3-dimethyl- 1 -butynyl)phthalonitde (25b)

was fomed. Unfomuiately, the retention tirnes of compounds 150 and 25b were too

close to separate using flash column chromatography. In order to prevent formation of

25 b we decided to use the dibrorno derivative 3,4-dibromophthalonitrile (123) instead.

The substitution of 123 under the same conditions as 117a led to the formation of the

desired product 150 and 4-(3,3-dimethyl- 1 -butynyl)-3-bromophthalle (152) in 40

and 45 % yields respectively (Scheme 25).

1 53

Scheme 25

Figure 9: Two possible isomers of AlPc that can be prepared fiom 153.

The tetramerization of 150 using lithium 1-pentoxiddl-pentanol at 135 O C aEorded

1,2,8,9,15,1 6,22,23scta(3,3-dimethyl- 1 -butynyl)phthaIocyanine (153) in 3 5 % yield. The

'H NMR spectra of Pc 153 exhibits two sharp doublets, as cm be expected for the one

isomer Pc. Pc 153 is much less soluble in organic solvents than its 2,3,9,10,16,17,23,24-

Pc isomer 141. The electronic spectrum for this Pc is shown in Figure 10. Pc 153 has a

M, (Qy) at 732 nm and its spectnim is very similar to that of 141. The synthesis of

metal derivatives of compound 153 is outside of this thesis but for the friture work it will

be interesthg to mention that replacement of interna1 hydrogens by trivalent metais such

as duminum will create a mixture of two optically active Pcs (Figure 9).

Figure 10: Electronic s p e c m for Pc 153.

The syntheses of binuclear phthalocyanines are traditional in our laboratory [30,35,56,

57,591. The preparation of such compounds is much more difficult than that for

mononuclear Pcs. Overail yields are not more than 5%, the preparations of the starting

materials are complicated and the final separatiom of the binuclear Pcs from products of

self-condensation are time consuming. For a number of years in our laboratory, 4-

neopentoxyphthalonihle (Sb) was exclusively used as a partner in the synthesis of

binuclear Pcs. The resulting binuclear Pcs are reasonably soluble in organic solvents and

phthalonitrile Sb can be prepared from commercially available 4-nitrophthalonitrile (6b)

in one step in good yield, and are easily obtained. In order to prevent foimation of

polynuclear Pcs, the ratio between bisphthalonitrile and phthalonitriles in the synthesis of

binuclear phthalocyanines must be as high as 1 to 20 and the partner phthalonitrile for the

binuclear Pcs spthesis mut be readily available in large amounts.

Al1 of the synthesized binuclear Pcs were obtained as mixtures of isomers. T'herefore, the

NMR data for such Pcs is Iimited to broad aromatic peaks, as representative of the spectra

of al1 isomers and the more informative signals for the interna1 protons. After

development of the synthesis of 4,5-diallrynylphthalonitri1es, we decided to use these

compounds as the partner for the mixed-condensation with bisphthalonitriles to obtain

binuclear Pcs as a single isomer.

We chose 4,s-(3',3'-dimethyl- 1 '-butyny1)p hthalonitnle (1 35) as the partner for the

synthesis of binuclear phthalonhiles because we expected that the bullcy 3,3dhnethyl-1-

butynyl groups would prevent aggregation, especially strong among the binuclear Pcs and

result in the highest solubility and easiest isolation of the desired compounds.

Aithough a number of binuclear phthdocyanines linked by bridges of different lengths

have been reported so far [30], they were mixtures of regioisomers, the presence of which

have made the interpretations of the observed physical or physicochemical properties

more difficult [98]. We decided to use one of the bisphthalonitriles synthesized in our

laboratory to prepare a single isomer binuclear Pc linked by 1,3-dialkoxy group (a five

atom bridge). The two phthalocyanine rings in this compound are not fixed in position

relative to each other and therefore are very mobile. We hoped that a NMR study of such

a compound would allow us to see the differences between the inûamolecular and

intermolecular interaction of the two macro rings of the binuclear Pc.

The synthesis of 1,3-bis-(3',4'-dicyanophenoxy)-2-ethyl-2-meylprope (73c) was

described in the introduction and is outlined in Scheme 12. The mixed condensation of

73c with a 20-fold excess of 135 with lithium 1-pentoxide in 1-pentanol at 100 OC gave

the binuclear metal-fkee phthalocyanine 1,3-bis-2'-(9', 10,16', 1 7',23',24'-hexakis(3",3"-

dimethyi- i "-butynyl)phthalocyanin0xy)-2~ethyI-2-methy1propaae (1 54) in 3.5% yield

(Scheme 26). Mononuclear metai-fiee phthalocyanine 141, which was formeci as a by-

product, had to be removed to puri@ the daired binuclear phthalocyanine.

As 141 is less soluble in THF than 154, the desired binuclear phthalocyanine was

effectively concentrated into THF solution fkom the reaction mixture. Attemptç to

separate the phthdocyanines h m each other by gel perrneation chromatography (GPC)

were unsuccessful because of poor resolution, maybe due to aggregation phenornena The

best separation was achieved by flash chromatography when it was pdormed on small

scale (less than 200 mg). The chromatographie separation on a large scale (>500 mg) was

unsuccessful because of the relatively low solubility of 154 in the solvent system

(toluenelhexane 1 : 1) used as the eluent. As expected, the binuclear Pc obtained in this

way was pure and was composed of only one isomer, as was shown by its NMR

spectnun. The NMR spectrum of 154 is characteristic for a heptasubstituted Pc and will

be descnbed in the next chapter of this thesis.

The electronic absorption spectrum of binuciear phthalocyanine 154 in O-dichlorobenzene

is shown in Figure 1 1. A quite broad absorption band was observed in the 600-700 nm

region with a maximum absorption at 698 nm. Dilution of the solution did not exhibit any

changes in its spectral patterns. Although the known mononuclear metal-fiee

phthdocyanines show a pair of sharp Q-bands in the same region (Figure 7) this is not the

case for 154. However, it is understandable that a close clam-shell conformation is

assumeci within the molecule because of a strong coupling between the two

chromophores of the Pc nuclei [98]. An alternative possibility that the binuclear

phthalocyanine molecules aggregate to each other even at this concentration range (10-5

mol/L) has been successfully eliminated by the NMR snidies described in the next

chapter. The syntheses descnbed in Scheme 26 were accomplished in cooperation with H.

Isago.

300 820 WAVELENGTH (nm)

Figure 11 : Electronic spectnim of binuclear Pc 154.

154 Scheme 26

Next, our target was to use commercially available 1,2,4,5-tetracyanobe~l~ene (5 1) as a

starhg materid for the synthesis of a single isomer fiat binuclear phthalocyanine. There

is considerab le interest in the synthesis and propertia of plana. binuclear

phthdocyanines sharing a cornmon benzene ring [60,99]. Some of these binuclear Pcs

have a electronic spectnun with maximum absorption above 800 nm and they were

studied as potentid electron transfer compounds [99] which can be used for many

applications where near IR absorption is necessary. Al1 of previously reported binuclear

Pcs sharing a comrnon benzene ring were mixtures of regioisorners and therefore, NMR

studies of such cornpounds were very limited.

A mixed condensation of 50 with a 20-fold excess of 135 with lithium 1-pentoxide in 1-

pentanol at 100 O C gave the binuclear metal-fiee phthalocyanine

b i ~ ( 7 ~ , 8 ~ , 1 32, 1 72, 1 82-hexakis(3i,3i-dimethY1-1'-butynyl)benzo[g,l,~-5, l0,15,20-

tetraazaporphyrinyl)[b,flbenzene (1 55) in 1.8% yield (Scherne 27). Mononuclear metal-

fiee phthalocyanine 141, which was fomed as a by- product, had to be removed to puri@

the desired binuclear phthaiocyanine. The usual sepration of binuclear Pcs begins with

two to three flash colums on silica gel to remove high molecular weight impurities, the

product of polyrnerization of phthdonitriles. Moremer, binuclear Pcs are generally less

soluble than mononuclear Pc and the nrst fiactions fiom the preiiminary columns

consisted mostly of mononuclear Pcs. We were very surpriseci when W analysis of the

£k t k t i o n s showed signincant amounts of binuclear Pc 155. Another interesting

property of Pc 155 is its colour. AU of the Pcs we synthesized before were green or blue.

This binuclear phthalocyanine was gray. Fractions consisting of 1 55 were coiiected

together and phthalocyanines 155 and 141 were easily separated fiom each other by gel

permeation chromatography (GPC). Despite a good separation of mononuclear and

binuclear phthdocyanines on a GPC column, the purification of the binuclear Pcs is a

very long and tedious procedure. For example, the maximum amount of a Pc mixture that

can be separated is no more than 60 mg. Therefore, for the isolation of 18 mg of binuclear

Pc we had to nin about 50 columns. We believe that relative size of Pc 155 in cornparison

with 141 is responsible for its good separation on a GPC column. The two binuclear

macrocycles in 154 (Scheme 26) folded together. Thus, the sizes of Pcs 154 and 141 are

very sirnilar and consequently, separation of these bndged Pcs by GPC chromatography

is impossible.

As expected, the isolated binuclear Pc 155 wnsists of only one isomer. The 'H NMR

spectra of this compound was very simple. The four intemal protons appeared at -2.32

ppm at a concentration of 2x1 O4 moVL (benzene-d,) and did not change with reducing the

concentration to îxlU5 mol&. Three singlets at 9.10,9.3 1 and 9.66 ppm conespond to

three different groups of protons (four each) at carbons "a", "b" and "c" (Scheme 27).

Two protons in the middie of the double macrocycle system appeared as a singlet at 1 1.30

ppm. Six groups of aliphatic protons (36 protons in each group) are represented by three

singlets at 1.79, 1.89 and 1.98 ppm. Unfortunately, binuclear Pc 155 is a very unstable

compound. Attempts to do variable temperature studies on this compound led to its

decomposition even at 80 OC. This explains the low isolateci yield of 155. M e r heating

this binuclear Pc in an NMR tube, we saw an irreversible change in the 'H NMR spectra.

Al1 aromatic signals transfomeci into one broad peak and the sepration between the

three aliphatic signals disappeared.

The electronic absorption spectnim of the binuclear phthalocyanine 155 in O-

dichlorobenzene is shown in Figure 12. A quite broad absorption band was observed in

the 600-800 nm region with an absorption maximum at 788 nm and two shoulden at

662,728 and 8 10 nm. The most intense sharp absorption band was observed at 885 nm.

Dilution of the solution did not exhibit any changes in its spectral patterns. Mer heating

the solution of binuclear Pc 155 at 80 OC for two hours the absorption s p e c m was taken

again. The broad band in the 600-800 nm region became stronger. The absorption peak at

885 nm became broader and a new absorption band appeared at 935 nm. Both the 'H

NMR and Vis/UV/IR data showed that themal decomposition of 155 did not affect the

macrocycles. The Iow energy bands in the VisNVIIR spectnun and the intemal protons

signals in the NMR spectnun did not disappear in the spectra of the decomposed 155.

Scheme 27

After heating

Figure 12: The electronic absorption spectrum of the binuclear phthalocyanine 155

before and d e r heating.

~ i s ( 7 ~ , 8 ~ , 1 22, 1 32, 1 72, 1 8 2 - h e x s ( 3 , 3 - e y l - l'-b~tyn~l)benzo[~,l,~-~, 10,l ~ J o -

tetraazaporphyrinyl)[b,flbenzene (155) was characterized by 'H NMR, W N i m and

MS, but we were unable to obtain a satisfactory elemental analysis of this compound

probably due to the low stability of 155.

Synthesis of bisphthalonitrües with aromatic bridges.

Two binuclear phthalocyanines cofaciaily linked by rigid naphthalene and anthracene

spacers 93 and 101 were synthesized in our laboratory [59]. Both binuclear Pcs were

isolated as mixtures of isomers because the non symrnetrical4-neopentoxyphthalonitnle

(ab) was used as the precursor partner for the mixed condensations. Moreover, the

naphthalene bndged Pc 93 was a mixture of two rotamers. Attempts at the separation of

the mixture using chromatographie methods were unsuccessîul. The 'H NMR spectra of

Pc 93 was not informative as might be expected for such a complicated isomeric mixture.

More detailed 'H NMR analysis of 1,8-bis(3,4-dicyanopheny1)naphthalene (91), the

precursor for the synthesis of 93, indicated that this compound exists at room temperature

as a 1 : 1 mixture of rotamers. It was suggested, that a separation of the two phthalonitrile

rotamen would not be useful since the high temperature of the Pc formation reaction

would interconvert the two rotamers. We examined the 'H NMR spectra of compound 91

at high temperatures and found that this suggestion was correct. At temperatures close to

86 OC the rotation barrier was broken and 91 appears as one compound. M e r cooling the

solution of 91 the 'H NMR spectra was completely restored without any indication of the

predominant formation any of the rotamers. These data correspond to detailed studies of

rotation barriers in 1,8-diarylnaphthalenes [100,10 11. When a hycûogen at C, of only one

p heny 1 group of 1,8-bisphenylnaphthalene was substituted by a substituent such as an

isopropyl or a carboxymethyl group, the rotation barrier was observed at Iower

temperatures [100,10 11. The substitution of a carboxy or carboxymethyl group of both

phenyl rings of 1,8-bisphenylnaphthalene heightened the rotation barria [102]. When a

hydrogen at C, of the phenyl groups was replaced by methyl, carboxymethyl or other

groups, the rotation barria was increased significantly and interconversion of the two

rotamers was observed only at temperatures as high as 145 OC [103]. Based on these

shidies, we proposed that the rotation barrier of 1,8-bisphenylnaphthalene with both

phenyl groups having cyano substituents at carbons 2 and 3 will be much higher than for

the bisphenylnaphthdene 91. Therefore, we should be able to separate the two

bisphthalonitrile rotamers prior to phthaiocyanine synthesis.

Scheme 28

The starting compounds for the formation of 1,8-bis(2,3-dicyanopheny1)naphthalene

(157) were synthesized in our laboratory (59). 3-Iodophthalonitrile (12a) was

synthesized fiom 3 -nitrophthdonitde (6a) in two steps [75]. 1,s-Diiodonaphthalene (90)

was made h m commercially available 1,8diaminonaphthaiene according to the

procedure d e s d e d by House et al. [102]. If a choice of starting materials was clear for

us, the method of diaryl coupling had to be investigated. AU diaryl couphg procedures,

where halogen aromatic compounds are used, can be divided into two groups: mixed-

condensation and cross-condensation methods. The rnixed-condensation of 90 and 4-

iodophthalonitrile (12b) using elemental nickel as a cataiyst gave the desired

bisphthdonitrile 91 only in 15.5% yield and the main products of this reaction were

products of self condensation of the starring matenais. The cross-condensation of 1.8-

dibromozincanthracene with 12 b gave 1,8-bis(3,4-dicyanopheny1)anthracene (99) in

9.9% yield as the only product 1591. We decided to reverse the steps of the cross-coupling

reaction used for the synthesis of 99. Iodophthalonitrile 12a was converteci into its

iodozinc derivative (156) using M c powder in an ultraçonic bath 11041. A cross-coupling

reaction between 1 56 and 90 catalyzed by tetrakis(tripheny1p hosphine)palladium gave

1,8-bis(2,3-dicyanopheny1)naphthalene (157) in 49.7% yield (Scheme 28).

'H NMR studies of this compound indicate that 157 exists as mixture of two rotamm.

The temperature 'H NMR andysis in DMSO-d6 did not show any indication of

interconversion of these two rotamers up to 150 OC. Attempts to separate these two

rotamers using flash chromatography rnethods were unsuccessful. One of the rotamers

was less stable in a solution of DMSO than the other. After staying for a couple weeks in

an NMR tube predominately one rotamer had decomposed. This phenornenon helped us

to assign the 'H NMR signals.

For the 1,8-disubstituted naphthalene systems, the two parallel phenyl rings are at an

angle of about 70" to the plane of the naphthalene ring, to relieve some of the strain in the

molecule [ 101,102]. The rotamer with two sets of cyano groups on the same side of the

naphthalene plane is refmed to as 157a and the other rotamer with cyano groups on the

opposite side is refmed to as 157b. Protodproton correlation experiments clearly

established the coupling relationship of the protons in the rotamen. The correlation

spectrum indicated the protons on the phenyl rings of 157a and 157b as separate systern

(Figure 14). The chernical shifts for protons on the naphthalene ring do not seem to be

affected by the different orientations of the phenyl rings. A mode1 based on the different

resultant dipoles pointed in different directions for 157a and 157b can hetp us to assign

Figure 13: Two possible rotamers of 157.

1 O3

the chernical shifts for the phenyl rings (Figure 13).The orientation on the resultant

dipoles may idluence the localkation of electron density over the ring and hence the

deshielding effect of the n cloud. For 157a , the resultant uuluence is located between

C2' and C3', which may have strong effect on H4' and less effect on H6'. The expected

chemical shifts are therefore H4' (doublet) > H6' (doublet) > H5' (doublet of doublets,

usually appears as triplet). For 157b, the resulting influence is concentrated between CS'

and C6', effecting the H5' and H6' almost equally and less than H4'. The nitrile groups

cause the phenyl protons to shifi downfield, which has much stronger effect on H4' in

both compounds and less effect on HS' and H6'. The expected chemical shifts order will

be the same, but chemical shifts for ail the protons in compound 157b will be closer to

each other. n i e pattern of the appearance of the naphthalene protons is the same as for the

phenyl protons as can be expected for an ABC system. The cornparison of the chemical

shifts of the naphthalene protons for compounds 157 and 91 and other 1.8-

dipheny haphthalenes allowed us to assign NMR signals to naphthalene protons as

follows: H4,5 at 8.2 ppm (doublet), H3,6 at 7.7 pprn (triplet) and H2,7 at 7.6 ppm

(doublet) (DMSO-d,). Now we can compare the two sets of signals that belong to the

phenyl protons of compounds 157a and 15%. The triplet at 7.3 ppm must belong to the

protons at CS' of compound 157a and the triplet at 8.0 ppm to the protons at C5' of lWb.

The nitrile groups in compound 1 S'la offset the chemical shift of protons at C S

downfield about 0.45 ppm. Compared to this, the chemical shift for these protons

observed in 1 ,8-diphenylnaphthalene occurred at 6.85 pprn in carbon tetrachloride. For

protons at C5' for 157b the effect of the nitrile groups is increased by the influence of the

deshielding effect of the two nitrile groups fiom the second phenyl ring. The chernical

shih for the protons at C4' and C6' for 157b is 8.3 and 8.2 ppm comspondingly. The

chernical shift for the protons at C4' for 157a is 8.25 ppm and for protons at C6' is 7.9

Figure 14: COSY experiment for compound 157.

Because we were not able to separate these two rotamers using column chromatography,

we decided to convert bisphthalonitrile 157 into a binuclear Pc and then attempt to

separate the Pc's rotamers ushg GPC. First we attempted to couple 157 with 135 in 1-

pentanoVlitbium 1-pmtoxide at 135 O C . MS and 'H NMR analysis of the resulting

mixture revealed the praence of only mononuclear Pc 141 and some mononuclear Pc as

products of incomplete reaction between 157 and 137. We suggested that it was

impossible to form a binuclear Pc because of steric hindrance. We supposed that the tert-

butyl group in 141 is too large to allowed binuclear Pc formation. Thus, 4,s-

diheptanylphthalonitnle (Hg), a very soluble phthdonitrile with long chah mobile

alkanyl groups, was chosen as a partner for the mixed-condensation with 157. Compound

158 was synthesized fiom phthalonhile 133 using the previously described catalytic

hydrogenation method. The condensation reaction between 157 and 158 did not lead to

the formation of binuclear Pc. Only mononuclear Pcs were found in the reaction mixture.

At this point we decided to stop our attempts to synthesis binuclear Pcs bndged with

naphthalene and anthracene. The steric hindrances of bis(2,3-dicyanopheny1)naphthalene

did not allow the desired Pc to be fonned. We suggested that the same effect would be

observed in attempted condensations 1'8-bis(2,3-dicyanopheny1)anthracene (159), but we

await confirmation of this in future work.

Some work was completed at this point in time toward the synthesis of 1,8-bis(2,3-

dicyanophenyl)antbracene (159) and we would like to report our results of this research.

The successful cross-coupling reaction between 90 and 12a indicated that the same

method for the synthesis of 159 be adopted (Scheme 29). The commercially available

1,8-dichloroanthraquinone (1 60) was converted to 1,8aiaminoanthraquinone (1 6 1) using

the procedure described by House and et al. [102]. In this work 161 was converted into

the 1 ,â-diiododerivative and the resulting compound was used to synthesize 1,8-

diphenylanthracene. In our case, it would be impossible to reduce the 1,8-

diphenylanthraquinone into 1'8-diphenylanthracene because of the presence of the cyano

groups. Therefore, we decided to reduce 161 into 1,8diaminoanthracene (1 63) using

sodium borohydride as a reducing agent in isopropanol. This reaction includes several

steps. The first one is reduction of the anthratquinone into l,8-diaminod, 1 O-

dihydroantbaquinone (1 62 a) with a following reduction into 1,8-diamino-9,lO-

dihidroanthracene (162b) and an aromatization reaction to form the final product. We

isolated trace amounts of 162a and 162b in the reaction mixture as bnght yellow

compounds. Compound 162a was very unstable and immediately after contact with air,

started to oxidize into the starhg material 161. The desired 163 was isolated as orange-

r d crystds after column chromatography and recrystallization fiom benzene in 46%

yield. Compound 163 was charactenzed by MS, 'H NMR and IR spectroscopy.

In the 'H NMR spectra (DMSO-d6) of 163 the four NH, protons' signal was observed at

5.55 ppm as a singlet, the protons at C, and C,, and protons at C, and C, appeared

together as a multiplet at 7.2 ppm, the protons at C2 and C, were observed as a doublet at

6.6 ppm. The signals of the protons at C, and C,, were observeci as singlets at 8.15 and

8.75 ppm correspondingly. We were using the same procedure for conversion of 163 into

1,8-düodoanthracene (164) as for the syntheses of 1,8diiodonaphthalene (92) fkom 1,8-

diaminonaphthalene [102]. Compound 163 was converted into its bisdiazonium salt by

treatment with N a N 4 in suliùric acid at -15 OC. The resulting mixture reacted with KI to

give 164 in 45% yield (Scherne 29). Compound 164 was characterized by MS. 'H NMR

and IR spectroscopy. The 'H NMR spectra of 164 consist of five signals: a singlet at 9.00

ppm for the proton at C,,, a singlet at 8.35 ppm for the proton at C, a doublet at 8.15 ppm

for the protons at C, and C,, a doublet at 8.05 ppm for the protons at C, and C, and a

triplet at 7.20 pprn for the protons at C, and C,. We did not couple this compound with

12a because of the unsuccessful attempts of the synthesis of binuclear Pc with 159.

Unforhmately, stenc hindrance did not allow us to synthesize binuclear phthalocyanines

with an aromatic bridge. The advantage of the hi& energy rotation barrier for 2,3-

dicyanophenylnaphthalene (157) becomes a disadvantage for binuclear Pc formation. The

alternative methods of fonnation of bisdicyanophenylnaphthalenes and

bisdicyanodiphenylanthracenes with sterically prohibited interconversion of two rotamers

is time consuming and lies outside the time fkme of this work. For future research, we

can suggest the use of 2,7-dimethyl- 1,84phenylanthracenes and 2,7-dimethyl-1,8-

diphenylnaphthalenes as alternative precusors for the synthesis of bndged binuclear Pcs

[104]. Two successfully synthesized phthalocyanines 154 and 155 are the first single

isomer binuclear Pcs. This fact makes the 'H NMR spectra of these cornpounds much

more informative for aggregation studies. The 'H NMR spectra of binuclear Pc 154 will

be discussed in the next chapter with the spectra of the newly synthesized metal fke and

metalated mononuclear Pcs.

Scheme 29

EFFECTS OF CONCENTRATION AND TEMPERATURE ON TTXE 'H NMR

SPECTRA OF PHTHALOCYANINES.

Our interest in the studies of temperature and concentration dependence of the chernical

shifts of aromatic and interna1 protons of phthdocyanines was initiateci by an interesting

obsenration during the characterization of octaallcynyl phthdocyanines. We expected that

thelH NMR spectra of the aromatic and interna1 protons in al1 octaalkynyl Pcs would be

very similar because the chernical environment for these protons is almost the same (with

the exception of the peripherai groups that are located far away fkom the Pc macro ring

and which shouid not have a large effect on the chemical shifts of the aromatic and

internai protons). Initial 'H NMR spectra obtained for Pcs at IO-* M in benzene-d, showed

that the internai protons of the tert-butylethynyl Pc 141 were M e r downfield than the

intemal protons of the other Pcs 137-140 at the same concentration. This observation can

be readily explained by the fact that the bulky tert-butylethynyl groups prevent

aggregation far better than to the linear alkynyl groups. These results b ~ g up an

interesting point. What is the actual absorption value of the intemal and aromatic protons

of an unaggregated Pc in a specific solvent? Our newly synthesized octaaikynyl Pcs are

excellent substances for this investigation because the 'H NMR spectra of these

compounds are very simple: one singlet for the two intemal protons, one singlet for the

eight aromatic protons and in the case of 141 one singlet for the seventy two identical

peripheral protons.

It was decided that a series of concentration and temperature 'H NMR studies wodd be

canied out on the octaallqmy1 metai free Pcs 137-141 and octaalkynyl zinc Pcs 144-148.

The results of these experiments are depicted in Figures 15-28. The effect of

concentration on the 'H NMR chemical shifts of the Pcs was studied over the

concentration range of 1 0-2-10-5 M in benzene-d6' The maximum concentration of the Pcs

was limited by their solubility, while the lowest concentration of the Pc was limited by

the acquisition tirnes on the NMR instrument available. It is apparent that for the intemal

NH protons, the chemical shift changes by almost 2 ppm downfield as the concentration

approaches 1 0'' M (Figure 15). At this latter concentration the Pc solution is alrnost

colourless, and 20 000 scans were required to obtain satisfactory spectra. The chemical

shift change with concentration is readily explained by the high aggregation [ I M , 1051 of

phthdocyanines and the fact that the cone of aromaticity of one Pc ring generally causes

an upfield shift of its aggregated partnen. It is likely that the aggregate dimers and

oligomers are not static in solution and cari slide over each other and rotate [106]. The 'H

NMR chernical shifts of the intemal and aromatic protons at high concentrations were

broad due to the formation of polymeric aggregates. When a solution of a Pc becomes

more and more diluted, the signals becomes sharper, which would be typicd for 'H NMR

spectra of rnonorneric species. At a Pc concentration about 1 0e3 M we oiten were able to

discem two peaks for intemal protons where the second peak had an intensity about 10%

that of the major peak. This peak actually disappears at both lower and higher

-4 -3 -2

Log ( m o n )

Figure 15. Plots of chernical shift of intemal protons of metal fiee phthdocyanines, as a

hinction of log concentration (moVL). 'H NMR in C a 6 at 27 O C : A (3,3-dimethyl-1-

butynyl) ,PcH2 141 , (1-hexynyl) ,PcH, 139, . (1-heptynyl) ,PcH2 138 ; V 'H NMR

in CDCI, at 27 OC : (3,3-dimethyl- 1 -butynyI) ,PcH, 14 1.

Figure 16. Plots of the chernical shift of the aromatic protons of metal f5ee

phthdocyanines, as a function of the log of the concentration (mol/L).

'H NMR in C a , at 27 OC : (3,3-dimethyl-1-butynyl),PcH, 141 ,@ (1-hexynyl),PcH,

139, A (1-heptynyl),PcH, 138 ; 'H NMR in CDCl, at 27 O C :V (39-dimethyl-1-

butynyl),PcH, 141, 'H NMR in Nitrobemene-d, at 27 OC: (3,341nethyl-1-

butynyl),PcH, 141.

Figure 17. Plots of the chernical shift of aromatic protons of zinc phthdocyanines, as a

function of the log of the concentration (molen). 'H NMR in C a 6 at 27 O C :

A (3,3-dimethyl- 1 -butynyl) ,PcZn 148 , (1 -hexynyl) ,PcZn 146, . (1 -0ctyny1) ,PcZn

144 .

concentrations and is probably due to discrete "dimer" aggregation where the signal for

the ''teminal" Pc will be different fiom that for the "intemal'' one.

As expected, the internai protons of 137-141 are more sensitive to changes of

concentration than the aromatic protons (Figure 16), since they are closer to the cone of

aromaticity in segregated species. StiU, the change of the chemical shift was very

significant and was about 1.5 ppm.

We also were interested in studying the effect of concentration on the 'H NMR chemical

shift of the zinc(II) octaaJkynyl phthalocyanines 144-148. For these Pcs we observe that

still there is a strong concentration dependence for hear -y1 Pcs 144-147 but that the

'H NMR chemical shifi of the aromatic protons of the tert-butylethynyl Pc 148 is only

slightly dependent on concentration Figure 17).

When a 5-1 0 tirnes excess of pyridine-d, or pyrazine was added to concentrated solution

of Pcs the 'H NMR chemical shifts of the aromatic protons of 144-148 approached the

value of the unaggregated Pc at 9.94-9.95 ppm in benzene-d,. With increasing the ratio

between pyrazine and 148 (increased to 5: 1) we were able to shifi the signal of the

aromatic protons of the Pc downfield f?om 9.75 ppm to 9.95 ppm (Figure 18). At the

sarne time with decreasing the concentration of pyrazine, the chemical shift of the

O 1 2 3 4 5 6

Ratio pyrazine/l48

Figure 18. 'H NMR chernical shift of the aromatic protons of ZnPc 148, as a fünction of

the pyrazine/l48 ratio in Ca, at 27 O C (Concentration of 148 is 1 . S X ~ O - ~ moyL).

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Ratio 1 Mfpyrazine

Figure 19. 'H NMR chernical shift of the protons of pyrazine, as a function of the

148/pyrazine ratio in C6D, at 27 OC (Concentration of 148 is 1 .SxlO" m o n ) .

Figure 20. Dependence on temperature of the chernical shifi of the aromatic protons of

metal fÏee (3,3-dirnethylbutynyl),PcH, 141 : in nitrobemene-d, (1.1 x IO-'), . in CDCI,

(3.6 x 109; in C P 6 : + 1.5 x 10" ,V4.0 x 104, A 9.4 x I ~ * ~ ~ O I / L

pyrazine protons was shifted upfield h m 8.0 ppm for pure pyrazine to 5.8 pprn when the

Pdpyrazine ratio was 2:l (Figure 19).

It was logical to assume that temperature will also affect the aggregation of

phthalocyanines and, hence influence the chemical shift of the intemal and aromatic

protons signals of Pcs. We couid use benzene or chlorofom only for temperatures below

70 OC because of their moderate boiling points. In order to investigate a wider

temperature range, we used nitrobemene-d, as a solvent. We found that dl our Pcs are

reasonably soluble in this solvent, especially at higher temperatures. Using a 1 0 ~ ~ M

concentration of 14 1, it was s h o w that the 'H NMR chemical shift of the aromatic

protons of 141 moved downfield fkom 9.30 ppm at 27 O C to 9.53 ppm at 137 O C at which

point no M e r downfield shifts occurred even at higher temperatures (Figure 20).

Similady, the 'H NMR chemical shifts of the internai protons shi fted kom - 1.35 pprn to

0.30 ppm at 157 OC at which point fllrther downfield shifb are less likely to occur (Figure

2 1). With increasing temperature, as with decreasing concentration, both aromatic and

intemal protons signals become sharper. In Figure 22 there is an example of the change of

the 'H NMR spectnun of Pc 141 upon varying the temperature. We noted that the

limiting downfield chemical shift for the aromatic protons of 141 at 105 M is 9.95 in

benzene-d,, which is different fiom that at 157 O C (9.73 ppm). We cm see that simply

raising the temperature of a concentrated solution is not entirely sufficient to deterrnine

the chemical shifi of "unaggregated " Pcs. In fact, at concentrations below I04M the

chemical shift of aromatic protons started to change upfield (Figure 20). It should be

noted that the aliphatic protons were unafkted by the effects of both concentration and

temperature. They are simply too far away from the Pc macrocycle.

Next we decided to do the same study with Pc 153, where we have two different groups

of protons: one is ortho to the aromatic Pc ring and the other is in the meta position

relative to the macrocycle. Ortho protons are similar to the aromatic protons in Pcs 137-

141 and one would expect the same behavior as for the arornatic protons of the previously

descnbed Pcs. The para protons are different and they are M e r away nom the centre of

the macrocycle than the ortho one. Unfominately, 153 was much less soluble in benzene

and nitrobenzene to do concentration and temperature dependence studies. The maximum

concentration we were able to reach was 104 moVL. As might be expected, there were no

changes in the chemical shifts of both signals of aromatic protons with changing the

temperature and the value for the signal of the para protons was 8.45 ppm and for the of

the ortho protons signal 9.65 ppm (Figure 23). On the other hand, the 'H NMR chemical

shift of the intemal protons exhibited changes with raising the temperature and moved

downfïeld Eorn -0.66 ppm at 77 O C to 0.05 ppm at 147 O C (Figure 24).

Temperature OC

Figure 21. Dependence on temperature of the chernical shifi of interna1 protons of metai

fiee phthalocyanines : (3,3-dhethyl- 1 -butynyI) B P ~ H 2 141 in C a 6 (different

concentrations) , . in nitrobenzene-d, (1.1 x 1 05), + in CDCI, ( 3.6 x 1 O"); V

(hexynyl),PcH, 139 in C P 6 (1.5 x A (1-heptynyl) ,PcH, 138 in Ca, (1.5 x 10-7.

Figure 22: Examples of change of the signals with changing a temperature for 141.

The 'H NMR spectra of binuclear Pc 155 is discussed in the previous chapter and it did

not exhibit any chemical shift with changes in concentration f?om 10 to 1 O-' m o n . We

were unable to do temperature studies for this compound due to thermal decomposition of

this binuclear Pc.

60 80 1 O0 120 140 160

Temperature O C

Figure 23. Dependence on temperature of the chemical shifi of the aromatic protons of

153 in nitrobemene-ds (1 X 1 o4 moVL): . protons 3,10,17,24 in the para position to

phthdocyanines ring , protons 4,11,18,25 in the ortho position to the aromatic ring.

70 80 90 100 110 120 130 140 150 160

Temperature O C

Figure 24. Dependence on temperature of the chernical shift of the interna1 protons of

153 in nitrobenzene-d, (1 x 1 o4 moVL).

-6 -5 4 -3 -2

Log (mollL)

Figure 25. Dependence on the concentration of the chernical shift of the intemal protons

of 154 in benzene-d,.

-4 -3

Log (rnollL)

Figure 26. Dependence on the concentration of the chernical shift of the aromatic protons

of 154 in benzene-d,.

The 'H NMR spectra of binuclear phthalocyanine 154 showed both temperature- and

concen~tion-dependence. The concentration dependence of the chemical shift of the

inner imino protons and some of the aromatic protons of the binuclear Pc 154 in benzene-

d, solutions are shown in Figures 25 and 26. Aithough the signal shified downfield in the

high concenttation region (lu2 - 104mol/L), it remaineci unchanged in the low

concentration region (1 O4 - 10 mol,L). For the rnononuclear phthalocyanines, the

chemical shifts of both intemal and aromatic protons shifted downfield as their

concentration was lowered fkom to 1 O6 m o n and no such saturation phenomena

against concentration was observed for any metal fiee mononuclear allcynyl Pcs.

Therefore, the saturation phenomenon is attributed to some preferred cofacial

conformation of the binuclear phthalocyanine 154 in solution .

A similar saturation phenomenon was observed when a nitrobenzene-d, solution

containhg the binuclear phthalocyanine 154 was heated to 147 "C (Figure 27). Although

the intemal protons did not show a clear saturation up to 147 OC, its chemical shift seerns

close to saturation around -2 ppm, the value of which is much lower than those of the

mononuclear Pc (Figure 21,24) at that temperature and concentration.

T'us, both the concentration- and temperature-dependence studies showed that the

chemical shift of the protons in binuclear Pc 154 reach constant chemical shift values at

higher concentrations and lower temperatures than the related mononuclear

1 O0 120

Temperature O C

Figure 27. Dependence on temperature of the chemical shift of the intemal protons of

154 in nitrobemene-d, ( 1 x 1 O4 mol/L).

60 80 1 O0 120 140 160

Temperature OC

Figure 28. Dependence on temperature of the chernical shift of the aromatic protons of

154 in nitrobenzene-d, (1 x 104 moYL).

phthalocyanines 137-141,153. These phenomena are rationalized by assuming two types

of interaction between the phthalocyanine macrocycles: one is an intermolecular

interaction between a phthalocyanine macrocycle molecule and that with other molecules

and another is an intramolecular interaction between the two macrocycles within a

molecule. In highly concentrated solutions, binuclear Pc molecules are close to each other

and hence col- of aggregated phthalocyanine macrocycles would be present in such a

solution.

Dilution of such a solution will lengthen the distance between phthdocyanines and hence

reduce the length of columns. Raishg the temperature would achieve the same effects on

the aggregated phthdocyanines because thermal motion of phthdocyanines would break

such columns and hence shorten their length. The shifis observed in the NMR spectra of

binuclear Pc 154 in this study either in highly concentrated solutions or at lower

temperatures could be explained in the same manner as the same phenomena for

mononuclear Pcs. On the other hand, neither the interna1 nor the aromatic protons showed

any shift in diluted solutions. This suggests that each binuclear phthalocyanine molecule

is ftee fiom any interaction with the other molecules. Nevertheless, the chernical shifts of

the inner protons of 154 plateau more upfield by 1 ppm than that of the mononuclear Pc

141 under the same conditions, indicating that a phthalocyanine macrocycle is still under

some type of interaction, which c m be attributable to intramolecular aggregation of the

two phthalocyanine macrocyclic rings in the molecule.

EXPERLMENTGL SECTION

General. Matheson high-purity argon was used to maintain ina atmosphere conditions.

h f k e d (IR) spectra were recorded on a Pye Unicam SP 1 O00 b f k e d spectrophotorneter

using D r discs. Nuclear magnetic resonance (NMR) spectm for proton and carbon were

recorded on a Bruker ARX400 NMR spectrometer at r o m temperature unless othenvise -.

stated. Teramethylsilane (TMS) was used as the interna standard. The positions of the

signals are reporteci in 6 units. The splittings of the signals are described as singiets (s),

doublets (d), triplets (t), quartets (q), pentets (p), sextets (h), doublets of doublets (dd), broad

(br), or multiplets (m). The ultraviolet-visible spectra (UV-vis) were recorded on a Varian

CARY 2400 spectrophotometer W-VIS-NIR. Mass spectra (MS) were recorded using a

Kratos Profile Mass Spectrometer in the EI mode for lower molecular weight molecules and

in the FAB mode, using m-nitrobenzyl alcohol as solvent for the phthalocyanines. The

number in parentheses d e r the indicated ion shows the percentage of the base peak

represented by that ion. Melting points (mp) were determined using a Kofler hot stage

melting point apparatus and are uncorrecteci. Flash chromatography was perfomied using

silica gel of particle size 20-45 mm. AU reactions were stirred with a magnetic stirrer.

Ultrasound activation was canied out using a Branson 1200 sonicator. Al1 solvents were

fieshly distillai before use. Microanalyses were p d o m e d by Guelph Chemical

Laboratory Ltd., Guelph, Ontario. niin-layer chromatography (TLC) was perfomed using

silica gel G as the absorbent.

4,5-Diiodophthallmide (115a) and 4,5-Diiodophthalic Acid (114). To 60 mL of 30%

fuming sulfùric acid was added 14.7 g (0.1 mol) of phthdimide (1 13) and 25.4 g (0.2 mol)

of iodine. The reaction mixture was heated to 75-80 O C for 24 h. This mixture was then

poured onto 400 g of ice and the precipitated soli& were filtered using a fiinne1 with a glas

fit. The solids were washed twice with water, once with a 2% solution of

&CO3, a saturated solution of N&O, and dried at room temperature. The soli& were

extracted with acetone (1 L) in a Soxhlet extractor for 48 h. The resulting precipitate which

fonned in the solvent vesse1 consisted of 4,5diiodophthalic acid (114) (mp 22û-2î0 O C , lit.

[79] mp 22 1-222 OC). Compound 114 was filtered nom the acetone and 100 mL of water

was added. This solution was concentrateci to 500 mL and cooled to give 20 g of a bnght-

yellow precipitate of 4,5-diiodophthalimide (115a). The mother liquon were reduced in

volume to 100 mL and cooled to give 15 g of a 4: 1 mixture of 115a and 114.

Chromatography on silica gel of this mixture using CHCI,-EtOAc (4: 1) as eluent gave 1 l5a

and 114 in total isolated yields of 75 and 20% respectively.

Compound 11 Ja: mp 297-299 OC; IR (KBr) 3 150 0 , 1 7 5 0 (Ce ) , 1700 (CIO) cm"; 'H

NMR (400 MHz, DMSO-d,) 6 8.25 (s, 2H), 1 1.41 (s, 1H); MS m/z (rd. Intensity ) 399

(M+, 82). Anal. Calcd for C,H31,N0,: C, 24.09; H, 0.76; N, 3.5 1. Found: C, 24.07; H,

0.66; N, 3.32.

4,SDiiodophthamide (116a). To 220 mL of conc. aqueou âmmonia was added 20 g (50

m o l ) of pure 4,5diiodophthaIimide (1 ISa). The rapidly stirred mixture was heated to 50-

60 OC for 1.5 h. The white solid was filtered and washed 3 thes with ice cold water and

with methanol to remove any trace arnounts of arnmonia and 115a. The solid was dried

ovemight at room temperature to give intermediate 1 16s (1 7.0 g, 8 1 %) as a white powder,

mp 297-299 O C ; IR (KBr) [3390,3280,31300], 1680,1640, (C=O)], 1590

1 , H NMR @MSO-d, 27 O C ) 6 7.91 (s, 2H), 7.80, 7.39 @s, 4H).

4,5=Diiodophthalonitrile (117a). To an ice-cooled stirred suspension of 8.3 g (20 m o l )

of 5 in 80 mL of dry dioxane and 18 mL of dry pyridine was added 16 mL of trifluoroacetic

anhydride at 0-5 OC. Mer the addition was complete, the reaction mixture was warmed to

room temperature, stirred ovemight, and p o d ont0 ice. The product was extracted 3 tirnes

with EtOAc. The organic layer was washed with water, 1 M HCl, dilute NqCO,, water and

dried over MgSO,. The solvent was removed under vacuum and the product was

recrystallized fiom ethanol to give 1178 (6.0 g, 79% yield) as yellow-white needles, mp

2 1 6-2 1 7 OC; IR (KBr) 22 1 0 (CN) cm-'; 'H NMR (CDCI,) G 8.1 9 (s); MS d z (rd intmity)

380 (M+, 100). Anal. Calcd. for C,H,I,N,: C, 25.29; H, 0.53; N, 7.37. Found: C, 25.6 1; H,

0.50; N, 7.24.

3,4-Düodophthalimide (1 15b), 34Düodophthalamide (116b) and 34-

Düodophthalonitriie (11%). When 113 was treated as above for the preparation of 115a,

but at 85-90 OC, an inseparable mixture of 1 lSa and 11% was obtained. This muchue was

treated as above for the preparation of 116a to give another inseparable mixture of 1168 and

1 l6b. Finally, treatment of 1 .O g of the mixhue of l l6a and 1 l6b as above for the

preparation of 1 l7a gave a mixture of 1 l7a and 1 lm. Separaiion of I l 7a and I l 7b on

silica gel chromatography using ethyl acetate-bexane (1 :9) as eluent, gave 1 l7a (0.8 g, 80%

yield) and 11 7b (0.1 g, 10% yield), mp 20 1-202 OC; IR (KBr) 22 15 (CN) cm"; 'H N M R

(CDCI,) S 8.19 (ci, J = 8.7 Hz, 1H), 7.80 (4 J = 8.7 Hz); MS m/z (relative intensity), 380

(M+, 89). Anal. Calcd forC,H,I,N,: C, 25.29; H, 0.53; N, 7.37. Found: C, 25.61; H, 0.51;

N, 7.24.

Dibromoisocyanuric Acid (120). The procedure of Gottardi [88] was used to prepare

compound 120: mp 320-321°C (lit. [88] rnp 306-307 OC).

3-Aminophthalonitrile (lla). Compound l l a was prepared h m 3-nitrophthdonitrile

(6a) as previously reported by Leznoff et al. [34] mp 200-202 O C (lit. 1341 mp 195-1 98°C).

3-Bromophthalonitrile (121). Compound l l a (0.5 g, 3.49 m o l ) was mixeci with 48%

hydrobromic acid (1 0 mL) and ice (24.7 g), and a solution of sodium nitrite (0.37 g, 5.5

mmol) in water (3.2 mL) was added in one portion. The resulting mixture was stirred for 2

hours in an ice bath. At the same t h e a solution of cuprous bromide was prepared by

dissolving anhydrous cupric sulfate crystals (1.0 g, 62.7 mmol) and potassium bromide (0.5

g, 4.20 mmol) in hot water (3 mL, 80 OC). To the tesuihg mixture a solution of sodium

metabidfite (0.2 g, 1 .O5 mmol) and sodium hydmxide (O. 1 g, 2.50 mmol) in wata (1.6

r d ) was added and stirred for 0.5 hours in an ice bath. The diazonium solution was poured

rapidly into the cold cuprous bromide solution and allowed to warrn to room tanperatine.

Once the solutions were thomughly mixed, 48% hydrobromic acid (1 mL) was added. The

resulting mkhm was s h e d for 2.3 hours. The mixture was extracted three times with

ether and the extract washed with water, a 1% solution of NaHCO,, a 1% solution of

NaHS03, water and dried over anhydrous MgSO,. M e r evaporation the mixture was

separated by silica gel chromatography using benzene as eluent and recrystallized fiom

benzene-hexane to give 121 (0.35 g, 45% yield) as white crystals: mp 15 1-1 52 O C ; IR (KBr)

2215 (CN) cm-'; 'H NMR (CDCI,) G 7.97 (lH, d, J=8.0 Hz); MS m/z (relative intensity),

206,208 w, 100%); Anal. Calcd. for C,H,BrN,: C, 46.4 1 ; H, 1.46; N, 13.53. Found: C,

46.34; H, 1 .l6; N, 13.54.

General Procedure for the Bromination of Phthaionitriie (3) and Brominated

Phthalonitrües 13,121427 with Dibromoisocyanuric Acid (120) in 30% Fuming

Soifuric Acid. Compound 120 was dissolved in 30% fuming sulfuric acid at room

temperature. Once dissolved, the solution was cooled in an ice bath and phthdonitrile (3)

or brominated phthdonitrile was added to the solution. The mixture was stined in an ice

bath for various tirne periods and then poured onto ice water. The resulthg mixture was

extracted 3 times with ether and the extract was washed with H,O, a 1 % solution of

NaKCO,, a 1% solution of NaHS03, water and dried over nnhydrous MgSO,. Evaporation

of the solvent gave a solid mixture which was subjected to HPLC using a gradient of H,Q

methanol(3:2, 1:1,2:3,3:7,0: 1) as eluent or separafeci by flash chrornatography on silica

gel using ethyl acetate-hexane (1: 19) to elute 3,4,5,6-tetraf,mmophthalonitrile (127), 3,4,5-

ûibrornophthalonitriie (126), 4,5-dibromophthalonitrile (124), 4bromophtbalonitrile (13) in

both pure and impure fiactions . Once TLC analysis indicated that 3,6-

dibromophthaonitrile (122) was starting to elute, the eluent was changed to ethyl acetate-

hexane (1 :4) to give 122, and 3 in both pure and impure fkactions.

Procedure for the 70 minute Reaction of 3 with 120. This procedure is the same as that

described in the general procedure above where 0.65 g (5.07 mmol) of 3 was added to

0.8 g (2.79 mrnol) of compound 120 dissolved in 3 mL of 30% fumuig sulfuric acid but the

mixture was dlowed to react for 70 minutes. A sarnple of 4.4 mg of the cmde mixture was

dissolved in 4.4 mL of methanol and 40 pL of this solution was subjected to HPLC. From

HPLC analysis it was detennined that the reaction mixture consisted of 3 (59.8 mg, 9.2%),

13 (6.3 mg, 0.6%), 121 (23.1 mg, 2.2%), 122 (33.4 mg, 2.3%), 123 (17.4 mg, 1.2%), 1124

(33.4 mg, 2.3%), 125 and 126 (35.6 mg, 1.9 %), 127 (4.5 mg, 0.2%).

Procedure for the 40 minute Reaction of 3 with 120. This procedure is the same as that

described in the general procedm above where 0.65 g (5.07 mrnol) of 3 was added to 0.8 g

(2.79 m o l ) of compound 120 dissolved in 3 mL of 30% fuming sulfunc acid but the

mixture was aliowed to react for 40 minutes. A ~ p l e of 3 .O mg of the m d e mixtrire was

dissolveci in 3.0 mL of methanol and 40 pL+ of this solution was subjected to HPLC. From

HPLC andysis it was detemiinai that the reaction mixture consisted of 3 (78.7 mg, 12.1%),

13 (9.5 mg, 0.9%), 121 (26.3 mg, 2.5%), 122 (42.1 mg, 2.9%), 123 (21.8 mg, 1.5%), 124

(42.1 mg, 2.9%), 125 and 126 (63.0 mg, 3.4 %), 127 (1 1.3 mg, 0.5%).

Procedure for the 30 minute Reaction of 3 with 120. This procedure is the same as that

described in the general procedure above where 0.65 g (5.07 mmol) of 3 was added to 0.8 g

(2.79 mmol) of compound 120 dissolved in 3 mL of 3 0% fîmhg sulfunc acid but the

mixture was allowed to react for 30 minutes. A sample of 4.9 mg of the crude mixture was

dissolved in 5.0 mL of methanol and 40 pL of this solution was subjected to HPLC. From

HPLC analysis it was determined that the reaction mixture consisted of 3 (104.7 mg,

16.1%), 13 (10.5 mg, 1.0%), 121 (26.3 mg, 2.5%), 122 (37.8 mg, 2.6%), 123 (21.8 mg,

1.5%), 124 (37.8 mg, 2.6%), 125 and 126 (109.4 mg, 5.9 %).

Procedure for the 20 minute Reaction of 3 with 120. This procedure is the same as that

described in the general procedure above where 0.8 g (2.79 mmol) of compound 120 was

dissolved in 3 mL of 30% fuming sulfuric acid. Once dissolved, the solution was cooled in

an ice bath and 0.65 g (5.07 m o l ) of 3 was added to the solution. The resulting mixture

was stirred in an ice bath for 20 minutes before being poured onto ice water. A sample of

5.2 mg of the crude mixture was dissolved in 5.0 rnL of methanol and 40 pL of this solution

was subjected to HPLC. From HPLC anaiysis it was detemiuied that the reaction mixture

consisted of 3 (122.4 mg, 15.3%), 13 (16.8 mg, 1.3%), 121 (47.9 mg, 3.7%), 122 (64.4 mg,

3.6%), 123 (39.3 mg, 2.2%)). 124 (64.4 mg, 3.6%), 125 and 126 (136.9 mg, 6.0 %), 127

(16.7 mg, 0.6%).

Procedure for the 11 minute Reaction of 3 with 120. A sample of 0.8 g (2.79 mmol) of

compound 120 was dissolved in 10 mL of 30% firming sulfunc acid. Once dissolved, the

solution was cooled in an ice bath and 0.65 g (5.07 m o l ) of 3 was added to the solution.

The resulting mixture was stirred in an ice bath for 1 1 minutes before being poured ont0 ice

water. A sample of 3.0 mg of the crude mixture was dissolved in 3.0 mL of methanol and

40 pL of this solution was subjected to HPLC. From HPLC analysis it was determined that

the reaction mixture consisted of 3 (210.4 mg, 26.3%), 13 (25.9 mg, 2.0%), 121 (49.2 mg,

3.8%), 122 (55.4 mg, 3.1%), 123 (39.3 mg, 2.2%), 124 (55.4 mg, 3.1%), 125 and 126 (84.4

mg, 3.7 %), 127 (1 1.1 mg, 0.4).

Procedure for the 1 minute Reaction of 3 with 120. A sample of 0.13 g (0.436 mmol) of

compound 120 was dissolved in 1.6 mL of 30% friming suifùric acid. Once dissolved, the

solution was cooled in an ice bath and 0.1 g (0.780 mmol) of 3 was added to the solution.

The resulting mixture was stirred in an ice bath for 1 minute before being poured onto ice

water. A sample of 3.0 mg of the crude mixture was dissolved in 1 .O mL of methanol and

40 pL of this solution was subjected to HPLC. From HPLC analysis it was determined that

the reaction mixture consisted of 3 (1 0.5 mg, 8.1 %)), 13 (2.1 mg, 1 .O%), 121 (2.7 mg, 1.3%),

122 (4.9 mgy 1.7%), 123 (3.5 mg, 1.2%), 124 (4.9 mg, 1.7%)). 125 and 126 (5.2 mg, 1.4 %),

127 (1.4 mg, 0.3).

Procedure for the Reaction of 121 with 120. A sample of 0.15 g (0.523 rnrnol) of

compound 120 was dissolved in 1.9 mL of fuming 30% sulfure acid. Once dissolved, the

solution was cooled in an ice bath and 0.22 g (1.06 mmol) of 121 was added to the solution.

The resulting mixture was stirred in an ice bath for 30 minutes before being poured onto ice

water. A sarnple of 4.3 mg of the d e mixture was dissolved in 10.0 mL of methanol and

40 pL of this solution was subjected to HPLC. From HPLC analysis it was detennined that

the reaction mixture consisted of 121 (8.3 mg, 5.5%), 122 (28.8 mg, 13.9%), 123 (3.3 mg,

1.6%), 125 and 126 (106.6 mg, 40.3%).

Procedure for the Reaction o f 13 with 120. A sample of 0.15 g (0.523 mmol) of

cornpolmd 120 was dissolved in 3 mL of 30% himùig sulfunc acid. Once dissolved, the

solution was cooled in an ice bath and 0.29 g (1.40 m o l ) of 13 was added to the solution.

The resulting mixture was stirred in an ice bath for 30 minutes before being poured onto ice

water. A sample of 5.0 mg of the cmde mixture was dissolved in 10.0 mL of methanol and

40 pL of this solution was subjected to HPLC. From HPLC analysis it was detennined that

the reaction mixture consisted of 13 (47.1 mg, 3 1.4%), 123 (2.5 mg, 1.2%), 124 (5.63 mg,

2.7%), 125 and 126 (44.7 mg, 16.9%).

Procedure for the Readion of 122 with 120. A sample of 22.6 mg (0.079 m o l ) of

compoimd 120 was dissolved in 0.5 mL of 30% fimiing sulfunc acid. Once dissolved, the

solution was cooled in an ice bath and 40.6 mg (0.142 m o l ) of 122 was added to the

solutio~~ The resuiting mixture was s&red in an ice bath for 5 minutes before h g poined

onto ice water. A sample of 1.1 mg of the crude mixture was dissolved in 2.0 mL of

rnethanol and 40 pL of this solution was subjected to HPLC. From HPLC analysis it was

deterrnined that the reaction mixture consisted of 122 (4.7 mg, 20.6%), 126 (8.0 mg,

27.7%), 127 (1.1 mg, 3.2%).

Procedure for the Reaction of 123 with 120. A sample of 55.5 mg (0.193 mmol) of

compound 120 was dissolved in 1 mL of fuming çulfunc acid. Once dissolved, the solution

was cooled in an ice bath and 100.9 mg (0.353 m o l ) of 123 was added to the solution. The

resulting mixture was stirred in an ice bath for 5 minutes before being poured onto ice

water. A sample of 1.4 mg of the crude mixture was dissolved in 2.8 mL of methanol and

40 pL of this solution was subjected to HPLC. From HPLC analysis it was detefmined that

the reaction mixture consisted of 123 ( 15.7 mg, 28.2%), 125 and 126 (20.0 mg, 28.3%),

127 ( 15.2 mg, 17.6%).

Procedure for the Reaction of 124 with 120. A sample of 55.6 mg (0.193 rnmol) of

compound 120 was dissolved in 1 mL of fuming 30% sulfunc acid. Once dissolved, the

solution was cooled in an ice bath and 100.1 mg (0.350 mmol) of 124 was added to the

solution. The resuIting mixture was st imd in an ice bath for 5 minutes before being poured

onto ice water. A sample of 2.5 mg of the cmde mixture was dissolved in 5.0 mL of

methanol and 40 pL of this solution was subjected to HPLC. From HPLC anaiysis it was

detexmineci that the reaction mixture wnsisted of 125 (1 1.6 mg, 16.4%), 127 ( 4.3 mg,

5.0%).

General Procedure for the Bromination of 3 with 120 in Concentrated Sulfuric Acid.

Cornpound 120 was dissolved with m g in concentrated sulfuric acid at room

temperature. Once dissolved, the solution was cooled in an ice bath and added in a few

portions to a stirred solution of 3 in concentrated sulfuric acid cooled in an ice bath. The

mixture was stirred in an ice bath for the various reaction times and then poured ont0 ice

water. The mixture was extracted three times with ether and the extract was washed with

water, a 1% solution of NaHC03, a 1% solution of NaHS03, water and dried over

anhydrous MgSO,. Evaporation of the solvent gave a solid mixture which was subjected to

HPLC using a gradient of H,O-methanol(3:2, 1:1,2:3,3:7,0:1) as eluent.

Procedure for the 2 hours reaction of 3 with 120 (2:l ratio). A sample of 1.5 g (523

rnmol) of compound 120 was dissolved in 40 mL of concentrated sulfunc acid. Once

dissolved, the solution was cooled in an ice bath and added in a few portions to a stirred

solution of 1.3 g (10.5 mmol) of phthdonitrile (3) in 20 mL of sulfunc acid in an ice bath.

The resuiting mixture was stirred 2 hours before being poured onto ice water. A sample of

2.3 mg of the crude mixture was dissolved in 5.0 mL of methanol and 40 pL of this solution

was subjected to HPLC. From HPLC analysis it was detennined that the reaction mixture

consisteci of 3 (885.0 mg, 59%), 13 (509.4 mg, 21%), 121 (291.1 mg, 12%), 122 (33.5 .ag,

l%), 123 (33.5 mg, 1%), 124 (33.5 mg, 1%).

Procedure for the 2 hours reaction of 3 with 120 (1.91 ratio). The same procedure was

used as described above for the 2:l ratio but using 0.98 g (7.9 mmol) of phthalonitrile (3). A

sample of 2.3 mg of the crude mixture was dissolved in 5.0 mL of methanol and 40 pL of

this solution was subjected to HPLC. From HPLC analysis it was detennined that the

reaction mixture consisted of 3 (431.2 mg, 44%), 13 (396.2 mg, 25%), 121 (174.3 mg,

il%), 122 (21.9 mg, 1%), 123 (21.9 mg, 1%), 124 (21.9 mg, 1%).

Procedure for the 2 honrs reaction of 3 with 120 (1:l ratio). The same procedure was

used as described above for the 2: 1 ratio using 0.67 g (5.23 mmol) of phthaloniûile (3). A

sample of 2.3 mg of the crude mixture was dissolved in 5.0 rnL of methanol and 40 pL of

this solution was subjected tu HPLC. Fmm HPLC analysis it was detennuied that the

reaction mixture consisted of 3 (120.6 mg, 18%), 13 (3 14.2 mg, 29%), 121 (1 30.0 mg,

12%),122 (44.9 mg, 3%), 123 (59.9 mg, 4%), 124 (44.9 mg, 3%), 125 and 126 (1 9.1 mg,

1 %).

Procedore for the 1 hour reacüon of 3 with 120. A sample of 3.2 g (1 1.2 m o l ) of

compound 120 was dissolved in 40 mL of concentrated M c acid. Once dissolved, the

solution was cooled Ui an ice bath and added in a few portions to a stirred solution of 1 A g

(1 1.2 mmol) of phthalonitriie (3) in 20 ml, of sulfunc acid in an ice bath. The resuiting

mixture was stirred 1 hour before being poureâ onto ice water. A sample of 4.2 mg of the

crude mixture was dissolved in 10.0 mL of methanol and 40 pL of this solution was

subjected to HPLC. From HPLC analysis it was determinai that the reaction mixture

consisted of 3 (244.0 mg, 16%), 13 (701.9 mg, 31%), 121 (271.7 g, 12%), 122 (62.6 mg,

2%), 123 (125.1 mg, 4%), 124 (62.6 mg, 2%), 125 and 126 (39.9 mg, 1%).

Procedure for the 30 minutes reaction of 3 with 120. A sample of 1.5 g (5.23 mmol) of

compound 120 was dissolved in 40 rnL of concentrated sulfuric acid. Once dissolved, the

solution was cooled in an ice bath and added in a few portions to a stirred solution of 0.67 g

(5.23 mmol) of phthdonitrile (3) in 20 mL of sulfuric acid in an ice bath. The resulting

mixture was sthed for 30 minutes before being poured ont0 ice water. A sample of 4.6 mg

of the crude mixture was dissolved in 10.0 mL of methanol and 40 pL of this solution was

subjected to HPLC. From HPLC analysis it was determined that the reaction mixture

consisted of 3 (1 13.9 mg, 17%), 13 (335.9 mg, 3 1%), 121 (1 19.2 mg, 1 1 %), 122 (29.9 mg,

2%), 123 (44.9 mg, 3%), 124 (29.9 mg, 2%), 125 and 126 (19.1 mg, 1%).

Procedure for the 20 minutes reaction of 3 with 120. The same procedure was used as

desmied above for 30 minutes. The d t i n g mixture was stirred for 20 minutes before

being poured onto ice water. Fmm HPLC analysis it was detexmineci that the reaction

mixture consisted of 3 (93.8 mg, 14%), 13 (314.2 mg, 29%), 121 (108.4 mg, 10%),122

(29.9 mg, 2%), 123 (29.9 mg, 2%). 124 (29.9 mg, 2%). 125 and 126 (19.1 mg, 1%).

Procedure for the 10 minutes reaction of 3 with 120. The same procedure was used as

described above for 30 minutes. The resulting mixture was stirred for 10 minutes before

being poured ont0 ice water. Fmm HPLC analysis it was detennined that the reaction

mixture consisted of 3 (140.7 mg, 21%), 13 (28 1.7 mg, 26%), 121 (108.4 mg, 10%),122

(15.0 mg, 1%), 123 (15.0 mg, 1%), 124 (15.0 mg, 1%), 125 and 126 (19.1 mg, 1%).

HPLC analysis. Phthdonitrile (3), 3-brornophthalonitrile (1 21), 4-bromophthalonitrile

(13), 3,6-dibromophthalonitnle (122), 3,4dibrornophthalonitnle (123), and 43-

dibrornophthalonitrile (124) reaction products were identified by cornparison of their

retention times to those observed for the previously isolated pure compounds. 3,4,5-

Tribromophthalonitrile (126) and 3,4,5,6-teMromophthaloni~1e (127) were identified by

cornparison of their retention times to those obsaved h m a mixture of 126 and 127.

Standard solutions consisting of 5.5 mg of 121,3.5 mg of 3,1.3 mg of 13, 1.6 mg of 122,

1.3 mg of 123, and 1.2 mg of 124 dissolved in 30 rnL of methanol and 4.0 mg of the

mixture containhg 126 and 127 dissolved in 20 mL of methanol were prepared respectively

and 40 pL of each solution was subjected to HPLC. Solutions of lmown concentrations of

the various reaction mixtures were aisa subjected to HPLC. The amount of each product

present in the various reaction mixtures was calcdated based on the peak height ratio of the

product to the standard. Isolation yields were detemiiaed by cornparison of the dcuiated

amounts of each product in the various mixhnes to the amount of stariing material used.

Procedure for the brornination of 3 with 120 in 8% furning sulfuric acid. A sample 8.6

g (30.0 mmol) of compound 120 was dissolved in 50 mL of 8% fûming sulfuric acid at

room temperahire. Once dissolved, the solution was cooled in an ice bath and 6.9 g (54.0

mmol) of 3 was added to the solution. The mixture was stirred in an ice bath for 5 minutes

before being poured ont0 ice water. The resulting mixture was extractecl 3 times with ether

and the extract was washed with H,O, a 1% solution of NaHCO,, a 1% solution of NaHSO,,

water and dried over anhydrous MgSO,. Evaporation of the solvent gave a solid mixture

which was separated by silica gel column chrornatography using a gradient of ethyl acetate-

hexane (1:19,1:4,0:1) as eluent to give a mixture of 126 and 127 (1.8%), a mixture of 121

and 3 (13%), 13 (45.2%), 122 (7%), 123 (5.9%) and 124 (6.7%).

Compound 122: rnp 250-252 O C ; IR (KBr) 2225 (CN) cm"; 'H NMR (CDCI,) G 7.78 (2H,

s); MS m/z (relative intensity), 286 (M+, 100%); Anal. Calcd. for C,H,BrN,: C, 33.60; H,

0.71; N, 9.80. Found: C, 33.57; H, 0.67; N, 9.60.

Compound 123: mp 164-165 OC; IR (Dr ) 2220 (CN) cm-'; 'H NMR (CDC13) 6 8.01 (lH,

d, J=8.7 Hz), 7.63 O1 (lH, d, J=8.7 Hz); MS mlz (relative intensity), 286 (M+, 80%); Anal.

Caicd. for C8H3BrN,: C, 33.60; H, 0.71; N, 9.80. Found: C, 33.50; H, 0.61; N, 9.73.

Compound 124: mp 2 14-216 OC; IR (KBr) 22 15 (CN) cm*'; 'H NMR (CDCiJ 6 8.07 (2H,

s); MS mlz (relative intensity), 286 (M+, 100%); And. Calcd. for C8H2Br&: C, 33.60; H,

0.71; N, 9.80. Found: C, 33.71; H, 0.51;N, 9.85.

4,5-Dibromopbtbalimide (128a).

To 60 rnL of 30% fuming sulfuric acid was added 14.7 g (0.1 mol) of phthahide (113),

32 g (0.2 mol) of bromine and 0.1 g of iodine as catalyst. The reaction mixture was heated

to 65-75 OC for 24 h and then air was bubbled through the solution to remove unreacted

bromine. This mixture was then poured onto 400 g of ice and the resulting suspension was

extracted by ethyl acetate 5 times. The combined organic layers were washed twice with

water, once with a 2% solution of K2C03, a saturateci solution of Na$,O, and dned using

MgSO,. The solvent was evaporated and the resulting solid was recrystallized fiom acetone

to give 10.8 g of pure 128a. Water was added to the mother liquor to precipitate 128. Mer

heating and cooling the resulting mixture, another k t i o n of 7.7 g. of pure 128a was

isolated. This procedure was repeated two more times to give an additional 3.5 g of pure

128a. The resulting solution contained mostly 128b (mp 243-245,lit.[8 11 mp 242-244 O C ) .

The overail yield of 128 was 72% mp 233-234 O C ; IR (KBr) 3140 (NH), 1740 (C=û), 1710

(Ce) cmœ1 ; 'H NMR (CDCI,) 6 8.1 1 (2H,s); MS mlz (relative intensity), 305 @f, 100%);

Anal. Calcd. forC,H,Br,N: C, 35.21; H, 1.11; N, 5.13. Found: C, 31.84; H, 0.77; N, 4.61.

4,5=Dibromophthalamide (129). To 90 mL of conc. aqueous ammonia was added 9.2 g

(30 rnmol) of pure 4,Sdibdophthalimide (128a). The rapidly stirred mixture was heated to

50-60 O C for 1 h. The white solid was filterd and washed 3 times with ice wld water and

with methanol to remove any trace amounts of ammonia and 128a. The solid was dried

ovemight at room temperature to give intermediate 129 (7.8 g, 80%) as a white powder, mp

240-243 O C ; IR (KBr) [3380,3275,3120(NH)], 1670,1630, (C=0)], 1580 cm-': 'H NMR

(DMSO-d,, 27 O C ) 6 7.90 (s, 2H), 7.80,7.39 (bs, 4H).

4,5=DibrornophthalonitriIe (124). To an ice-cooled &ed suspension of 5.6 g (1 7.4

mmol) of 130 in 50 rnL of dry dioxane and 1 1.5 mL of dry pyridine was added 10.2 mL of

trifluoroacetic anhydride at 0-5 OC. After the addition was complete, the reaction mixture

was warmed to room temperature, stirred ovemight, and poured ont0 ice. The product was

extracted 3 times with EtOAc. The organic layer was washed with water, 1 M HCI, dilute

Na$O,, water and dried over MgSO,. The solvent was removed under vacuum and the

product was recrystallized h m ethanol to give 124 (4.2 g, 85% yield) as white needles, mp

214-216 OC.

3,5-Dibrom&hydroxyphthalonitrfle (130a), 4-bromo-lhydroxyphthalonitrile

(130b), 3-brom&hydroxyphthalonitrile (13Oc). Into a solution of 7.8 g of 4-

hydroxyphthalonitrile ( l m ) (54.2 m o l ) in 100 mL of concentrated H,SO, was added a

solution of 10 g of N,N-dibromoisocyanuric acid (NBI) (35.2 m o l ) in lOOmL of

concentrated H2S04. The mixture was stirred for 10 min and then poured onto 800 g of

ice. The resulting precipitate was filtered and the filtrate was extracted 3 times with ethyl

acetate. The extract was washed with water, a 2% solution of NaHCO,, water again and

dried with MgSO,. The solvent was removed by rotoevaporation. The resulting mixture

was separated by column chromatography on silica gel (ethyl acetate) to give 2 g of 3-5-

dibromo-4-hydroxyphthalonitrile (130a) (yield 12 %). mp 269-271 O C ; IR (KBr) 3280

(OH), 2214 (CN) cm"; 'H NMR (DMSO-d,) 6 1 1 .16 (IH, s, O-H), 8.38 (lH, s, H-C6); MS

d z (relative intensity), 302 (M+, 100%); Anal. Calcd. for C,H2Br2N20: C, 3 1.83; H, 0.65;

N79.28.Found:C,31.84;H, 0.65;N,9.00.

Further elution with ethyl acetate and evaporation of the solvent gave 2.1 g of a mixture

of monobromo isomers. The original precipitate was extracted 4 times with ethyl acetate

(leaving a residue of isocyanuric acid) and the extract was dried, filtered, and evaporated

as above to give an additional 6.6 g for an overall yield of 72% of an inseparable mixture

of 5-bromo-4-hydroxyphthalonitnle (1 30b) and 3-bromo-4-hydroxyphthdonitrile (1 30c).

'H NMR (DMSO- d,) 6 1 1.16 (IH, S, O-H), 8.39 (lH, S, BC6 (130b)),8.08 (1 H, S, H-

C3(130b)), 7.81 (lH, d, HOC6 (130~)), 7.30 (lH, d, H-C5 (130~)).

5-Brom&butoxyp hthalonitriIe (13 1 a) and 3-bromo4butoxyphthaIonitrile (131 b).

To 50 mL of DMF was added 4.0 g (18 mmol) of the mixture of l3Ob and 130c (18

mmol) ,4.7 g. of K2C03 and 4.5 g of 1 -bromobutane. The mixture was stirred at 90 OC for

2 h and then poured into 200 mL of water. The mixture was extracteci twice with benzene

and the extract washed twice with water and dried over anhydrous MgSO,. The solvent

was evaporated to give 7.6 g of a solid mixture. The mixture was separated by flash

column chromatography on silica gel using benzene-hexane (1 : 1) as eluent to give, in the

first hctions in 34% yield, 1.7 g of 5-bromo4butoxyphthalonitri1e (13 1 b) mp 1 1 7- 1 19

OC; IR (KBr) 2230 (0 cm"; 'H NMR (CDCI,) 6 7.93 (lH, s, H-C6), 7.1 8 (IH, s, H-C3),

4.13 (2H, t, J = 4.2 Hz, OCHJ, 1.88 (2H, m, OCH,CHJ, 1 S6 (2H, m, CH,CHJ, 1 .O 1 (3H,

t, J = 4.9 Hz, CH,); MS m/z (relative intensity), 278 (M+, 3 1%); Anal. Calcd. for

C1,H,,BrN2O: C, 5 1.64; H, 3.86; N, 9.95. Found: C, 52.04; H, 4.03; N, 10.02.

Further elution gave 1.5 g of 3-bromo4butoxyphthalonitrile (131a) in 30% yield mp

116-1 17 OC; IR (Dr) 2235 (CN) cm"; 'H NMR (CDCI,) G 7.79 (lH, d, J = 5.8 Hz, H-C6),

7.1 1 (lH, d, J = 5.8 Hz, H-C5), 4.14 (2H, t, J 4 . 2 Hz, OCHJ, 1.87 (W, m, OCH,CHJ,

1.55 (W, m, CH,CHJ, 1 .O0 (3H, t, J = 4.9 Hz, CH,); MS m/z (relative intensity), 278 (M+,

76%); Anal. Calcd. for C12H, ,BrN,O: C, 5 1.64; H, 3.86; N, 9.95. Found: C, 5 1.76; H, 3.86;

N, 9.95.

4~Di(l-octynyI)phthalonitrile (132). Generd Procedore. To a solution of 500 mg (1.3

mmol) of 4,5-d.iiodophthalonitde (1 l'la) dissolved in 20 mL of TEA was added 580 mg

(5.3 mmol) of 1-octyne and a 5% molar amount of Pd(PPhJ2C12. The reaction was heated to

1 10 OC under argon. The d o n was monitored by TLC using hexane-benzene (1 : 1) as

eluent M e r 30 min ali of the starting phthalonitrile had wmpletely reacted and the reaction

was cooled to room temperature. The reaction m i . was then suction filtered on a glas

fitted bel, and the collected precipitate was washed with diethyl ether until the filtrate

was colourless. The filtrate was then evaporated to dryness under reduced pressure and then

preabsohed onto classical silica-gel . A column using classical silica-gel with n-hexane as

eluent removed al1 unreacted 1-octyne. The solvent was then changed to hexane-benzene

(1 : 1), and the first Faction collected (280 mg) was the desired product. This product was

fiuthm purified by recrystallization in n-hexane to give a wâxy yellow solid in 68% yield:

mp 42-44 OC; 'H NMR (CDC13) 6 7.72 (s, 2H), 2.49 (t, J = 7.0 Hz, 4H), 1.59 (m, 4H), 1.45

(m, 4H), 1.3 1 (m, 8H), 0.90 (t, J = 6.7 Hz, 6H); IR (KBr) 2930 (s), 2230 (s), 1500 (s) cm-';

MS d z 344 (70), 259 (50), 245 (80), 23 1 (95),2 17 (1 OO), 203 (go), 19 1 (85), 179 (75).

Anal. Calcd for C&I,,N,: C, 83.67; H, 8.14; N, 8.14. Found: C, 83.38; H, 8.23; N, 8.17.

4.IDi(l-heptyny1)phthalonitrile (133). The same procedure as descnbed above for 132,

fiom 117a and I-heptyne was used to prepare 133 in 80% yield: mp 42-43 O C ; 'H NMR

(CDC1,) 6 7.7 1 (s, 2H), 2.49 (t, J = 7.0 Hz, 4H), 1.60 (m, 4H), 1.44 (m, 4H), 1.36 (m, 4H),

0.92 (t, J = 6.8 Hz, 6H); IR (KBr) 2958 (s), 2861 (m), 2229 (s), 1589 (m) cm-' ; MS mlr 316

(M+, 73). Anal. Calcd for C&24N2: C, 83.50; H, 7.64; N, 8.85. Found: C, 83.75; H, 7.80;

N, 8.91.

4,s-Di(1-hexynyl)phtùaIoniMe (134). The same procedure as d d b e d above for 132

using 1 g of 4,s-diiodophthaloniûile (1 l7a) and 1-hexyne was us&. Mer the reaction was

complete, the reaction mixture was diluted with toluene and washed in a separatory k e l

once with water, then once with brine and again with water. The organic layer was then

jned over MgSO,. To the toluene layer was added 1.5 g of classical silica-gel, the toluene

was removed under reduced pressure. A classical silica-gel colurnn using toluene as eluent

gave two h t i o n s , the first was unreacted 1-hexyiie and the second was the d e s a product

134 in 76 % yield: mp 84-86 O C ; 'H NMR (CDCIJ 6 7.71 (s, 2H,),2.50 (t, J = 7.0 Hz, 4H),

1.61 (m, 4H), 1.49 (m, 4H), 0.95 (t, J = 6.8 Hz, 6 ' ) ; IR (KBr) 2957 (s), 2873 (m), 2227 (s),

1 589 (m) cm"; MS m/z 288 (M+, 5 8). Anal. Calcd. for C2J12&: C, 83.30; H, 6.99; N,

9.71. Found: C, 83.59; H, 7.10; N, 9.78.

4,5Di(lDpentyny1)phthslonitrile (135). The same procedure as descnbed for 132 was used

f h m Il7a and 1-pentyne to give 135 in 82% yield: mp 102-104 O C ; 'H NMR (CDClJ ,)G

7.73 (s, 2H). 2.50 (t, J = 7.0 Hz, 4H), 1.65 (m, 4H), 1.07 (t, J = 6.9 Hz, 6H); IR (KBr) 2974

(s), 2878 (m), 2230 (s), 1585 (m) cm-1 ; MS m/z 260 (M+, 100). Anal. Calcd for C,,H,,N,:

C, 83.04; H, 6.19; N, 10.76. Found: C, 82.88; H, 6.24; N, 10.85.

4&Di(3J4imethyi-l-butynyl)phthalonitrile (136). To a solution of 60 mL of TEA was

dissolved 1 g (2.6 mmol) of 4,5,-diiodophthalonitrile (1 1 fa), 0.53 g (6.5 mmol) of 3,3-

dirnethyl-1-butyne, (3.75 mmol) Cu1 and 60 mg of Pd(PPh3kC1,. AU reactants were dowed

to stir under argon at room temperature. The reaction was monitored by TLC (with hexane-

benzene (1 : 1) as the eluting solvent), and after 1 h most of the starting material had reacted.

At this point an additional 0.3 g of alkyne dong with 0.1 g of Cul and 40 mg of W y s t was

added. Mer 6 h the reaction was complete. The reaction mixture was suction filtered on a

glass fritted funne1 and the collected precipitate was washed with diethyl ether unâil the

filtrate was colourless. The filtrate was then evaporated under reduced pressure to give an

orange solid which was recrystallized h m hexane to give 63 5 mg of 136 as white crystals

in 85% yield: mp 177-1 79 O C ; 'H NMR (CDCI,) 6 7.82 (s, ZH), 1.36, (s, 18H); IR (Dr )

2230 (CN) cm-1; MS mh 288 (hl+, 78). Anal. Calcd for C,,,H282: C, 83.30; H, 6.99; N,

9.71. Found C, 83.30; H, 7.12; N, 9.55.

4*Di(3J-dimethyC1-butyny1)phthalonitrile (136) (alternative synthesis).

To a solution of 0.5 mL (4 mmol) of 3,3-dimethyl-1-butyne in 2 mL of dry TKF at -5 OC

was added 4 mm01 (2 mL of a 2M solution in pentane) of n-BuLi. The solution was stirred

for 5 min followed by the addition of 545 mg (4 mmol) of anhydrous ZnC1, dissolved in 4

mL of THF. The mixture was stirred for an additional 15 min at room temperature. To this

mixture were added at O O C 760 mg of 1 l f a (2 mmol) dissolved in 4 mL of THF and 230

mg of tetrakis(triphenylphosphine)palladium(O) in 4 mL of THF and the resultkg mixture

was stirred for 2 hours at room temperature. The solvent was evaporated and the solid

residue was extracted with baizene. The extract was evaporated and 136 was separated

h m impurities h g flash column chromatography as described above to give 490 mg of

136 as white crystals in 85% yield-

2,3,9,10,16,17,23,24-0cta(1-o~tynyr)phthal0cyanine (137). To 2.5 mL of 1-pentmol was

added 30 mg of lithium metal and the solution was stirred under argon at 60 OC. Mer all of

the lithium metal had dissolved, the solution was cooled to room temperature and 300 mg

of 132 was added. The reaction mixture was then heated to 1 10 OC under argon. The

reaction was monitored by TLC with benzene as eluent. After 3 h all of the starting

phthdonitrile 132 was gone, the reaction was then cooled to mom temperature and diluted

with 10 rnL of 20% methanoWwater. Mer 90 min the reaction mumire was then centrifugai

and the precipitate collected. The precipitate was fiirther washed with methanol and

collected by centrifugation. This process was continued until the filtrate was colourless. At

this point the crude pigment was m e r purified by flash column chromatography using

benzene as eluent. The first band collected was the desired Pc 137 and was m e r purified

by a second fia& silica-gel column to rernove all insoluble impmitia. Final purification

involved the reprecipitation of 137 h m THFIethanol which gave the desired Pc in 43%

yield: 'H NMR (benzene-d, 1.5 x 1 O5 M, 27 OC) 6 8.77 (s, 8H), 2.8 (t, J = 6.9 Hz, 16H),

1.9 (m, 16H), 1.65 (m, J = H z , 16 H), 1.5 (m, 32H), 1.1 (t, J = 7.1 Hz, 24H) -2.38 (br, 2H);

W-vis h,, (THF) (log e) 730 ( 5 4 , 6 9 4 (5.38), 636 (4.89), 364 (5.29) nm; FABMS

1379 (M+l, 40). Anal. Calcd for C&,,,N,: C 83.59; H 8.27; N 8.13. Found: C, 84-15; H,

8.40; N, 8.23.

2,3,9,10,16,17,23,24-Octa(l-hep~yr)phthalocyanine (138). Pc 138 was prepared using

the same method as dacribed above using 200 mg of 133 to give 76 mg of 138 in 38%

yield: 'H NMR (benzene-d, 1 O4 M, 27 OC) S 9.14 (s, 8H), 2.82 (t, J = 6.9 Hi, 1 6H), 1.92

(m, 16H), 1.67 (q, 16H), 1.5 (m, l6H), 1.1 (f J = 7.1 Hz. 24H), -2.65 (bs, 2H); W-vis h

(THF) (log e) 730 (S.47), 694 (539,636 (4.92), 364 (5.32) nm; FABMS 1266 (M+l).

Anal. Cdcd for C&&&: C, 83.33; H, 7.79; N, 8.84. Found : C, 82.67; H, 7.12; N, 9.39.

2$,9,lO,l6,l 7,23 f 4-Octa(1-henyny1)phthalocyanhe (139). The same method as

descnbed above for 137 was used, except that 100 mg of 134 was used to give 40 mg of

139 in 40% yield: 'H NMR (benzene-d, 1.5 x IO', M, 27 OC) 6 8.73 (s, 8H), 2.83 (t, J = 6.6

Hz, 16H), 1.92 (m, lm, 1.8 (m, l6H), 1.15 (4 J = 7.4 Hz, 24H) -2.82 (br, 2H); UV-vis

hax (m) (log e) 730 (5.22), 694 (5.19), 366 (5.04 nm); FABMS 1154 (M+l). Anal.

Calcd for C&,,N,: C, 83-15; H, 7.15; N, 9.70. Found: C, 82.98; H, 7.76; N, 8.68.

2,3,9,10,16,17,23 J4Octa(l-pentyny1)phthalocyanhe (140). The sarne method as

described above for 137 was used except that 250 mg of 135 was used. As a result of the

poor solubility of the desired Pc 140, it was necessary to use CHCI, as the eluent for flash

column chromatography instead of benzene. Two columns wae run on the crude pigment

and the final product was reprecipitated h m THF/ethanol to give 75 mg of the desired Pc

140 in 30 % yield: 'H NMR (benzene-d,, 1.8 x IO-' M, 27 OC) 6 8.79 (s, 8H), 2.88 (t, J = 6.9

16H), 2-03 (W 16H), 1.44 (t, J = 7.4 Hz, 24 H), -2.64 (br, 2H); W-vis hm,

Oog e) 728 (5.03). 694 (5.00), 628 (4.55),363 (4.27) nm; FABMS 1042 (M+1).

2~~10,16,17J3~cta(3,3aimethyl-l-butynyi)ph~aloeymine (141). The same

method as describeci above using 100 mg of 137 gave 36 mg of 136 in 36% yield: 'H NMR

(400 MHz, benzene-d, 1.5 x 27 O C ) 6 9.44 (s, 8H), 1.45 (s, 72H), -1.42 (br, 2H); W-

"s (CHCI,) (log e) 734 (5.32), 694 (5.27), 666 (4.72), 632 (459,368 (5.03), 314

(4.89) m; FAB MS (M+l, 1154). Anal. Calcd for C&g2N8: C, 83.15; H, 7.15; N, 8.68.

Found: C, 82.98; H, 7.76; N, 8.68.

2~,9,lû,l6,~7,t3,24-Octa(l-octynyI)phthalocyanine zinc (II) (144). To 2.5 mL of 1 -

pentanol was added 30 mg of lithium metal. The solution was stirred under argon at 60 OC

until al1 of the lithium had dissolved. At this point the alkoxide solution was cooled to room

temperature and 250 mg of 137 was added. The reaction mixture was then heated under

argon to 1 10 OC for 3 h. After this tirne the reaction temperature was lowered to 80 OC and

300 mg of Z~(OAC)~ was added. The reaction mixture was allowed to stir for an additional

2 h at 80 OC. The reaction mixture was then cooled to room temperature and diluted with 10

mL of 20% methanol/water. Mer standing for 90 min the reaction mixture was centrifuged

and the m d e zinc Pc 144 collected. The crude pigment was M e r washed with 20%

methanoVwater until the filtrate was colourless. It was then washed with methanol and

acetooitrile. The crude Pc 144 was fiuther purified by flash column chromatography with

benzene as eluent and the M band coliected was the desired Pc. This material was finther

purifiai by a second flash silica-gel column with bcnzene as eluent to give 100 mg of the

desired 144 in 40% yield: 'H NMR (benzene4,1.6 x 10') M, 27 OC) 6 8.68 (s, 8H), 2.8 1 (t,

J = 6.8 HZ, EH), 1.95 (m, MH), 1-77 (m, 16H), 1.62 (m, XH), 1.16 (t, J = 7.1 Hz, XH);

W-vis & (log e) 708 (5.57), 636 (4.81), 370 (5.21) nm; FABMS 1444.6 (M+l).

Anal. Calcd for C&4,2N+: C, 79.75; H, 7.75; N, 7.75. Found: C, 79.40; H, 7.88; N, 7.73.

2,3,9,iO,i6,17,23,24-Octa(l-heptynyI)phthalocyani.e zinc ('II) (145). The same

procedure as described above to make 144 was used to give 112 mg of 145 in 45% yield:

'H NMR (benzene- d,, 1.5 x M) 6 8.85 (s, 8H), 2.80 (t, J = 7.1 Hz, 16H), 1.95 (m,

16H), 1.77 (m, 16H), 1.63 (m, 16H), 1.18 (t, J = 6.9 Hz, 24H); UV-vis (THF) (log e)

706 (5.54), 636 (4.77), 370 (5.12) nm; FABMS 1329.8 (M+l). Anal. Calcd for

Ca8&NaZn: C, 79.41; H, 7.22; N, 8.42. FOU^^: C, 79.47; H, 7.27; N, 8.16.

2,3,9,lO,l6,l7,23J~-Octa(l-hexynyi)ph thalocyane zinc (II) (146). The same

procedure as outlined above for 144 was used to give 95 mg of 146 in 38% yield: 'H NMR

(benzene- d , 1.6 x 1 o - ~ M, 27 OC) 6 8.73 (s, 8H), 2.83 (t, J = 7.1 Hz, 1 6H), 1.96 (rn, 16H),

1.85 (m, 16H), 1.21 (î, J = 6.9 Hz, 24H); UV-Vis (THF) (log e) 708 (5.52), 634

(4.73), 370 (5.12) nm; FABMS 1216.9 (M+l). Anal. Calcd for C8&&&

C, 78.83; H, 6.62; N, 9.19. Found: C, 79.36; H, 6.92; N, 8.72.

2,3,9,10,16,17,23,24-0cta(l-pentynyI)phhbpnhe zinc 0 (147). The same

procedure as descn'bed above for 144 was used, that except mcI3 was used a s eluent

instead of benzene for column chromatography to give 147 in 38% yield: 'H NMR

(pyridine-d, 10-4 M,27 OC) S 9.79 (s, 8H), 2.84 (t, J = 7.1 Hz, 16H), 1.96 (m, 16H), 1-27 (t,

J = 6.9 Hz, 24H); UV-vis & (TEIF) (log e) 706 (549,638 (4.74), 368 (5.14) mn;

FABMS 1108 (M+l). Anal. Calcd for Cn&N8Zn : C, 78.05; H, 5.78; N, 10.12. Found: C,

78.16; H, 5.86; N, 10.12.

Synthesis of octa(3 J-dimethyl-1-butynyi)phthslocymhe zinc (II) (148).

The same procedure as outhed above was used to give 148 in 25% yield. 'H NMR (400

MHz, benzene-d, 2.7 x loJ) 6 9.74 (s, 8H), 1.46 (s, 72H); &, (CHCI,) (log e) 714

(5.40), 640 (4.6 1), 370 (5.00) nm; FAB MS (M+l) 1216.9. Anal. Calcd. for C,,,H8&Zn: C,

78.83; H, 6.62; N, 9.19. Found: C, 77.94; H, 6.62; N, 8.57.

4-Iodo-5-(octyny1)phthalonitrile (149). To a solution of 3.8 g (10 m o l ) of 4,s-

diiodophthalonitrile (1 17a) dissolved in a 40 mL mixture of TEA and DMF (1 : 1) was added

3 mL (20 m o l ) of 1-octyne and a 5% molar amount of Pd(PPhJ2C12. The reaction mixture

was heated to 100 O C under argon, for one hour, woled to room temperature, and diluted

with 200 mL of ethyl acetate, and extracted 3 times with water, 5% HC1, water, a 2%

solution of NaHCO,, water, and dried with MgSO,. The solvent was evaporated under

reduced pressure, and the oil residue was separated by column chromatography on silica

gel, using hexane and ethyl acetate (1 9: 1) to give 4,5-düoctynyIphthalonitri1e (132) (1 -4 g,

40%) and 4-iodo-5-(1-0ctynyi)phtiialonitrile (149) 1.1 g (30%) as white needles: mp 46-47

OC; IR QBr) 2256,2210 cm-'; 'H NMR (CDCIJ G 8.19, (s, lH), 7.21, (s, IH), 2.86 (5 J =

7.0 Hz, 2H) 2.69, (m, 2H), 1 S2 (m, 2H) 1.33, (m, 2H) 0.93, (5 J = 6.8 -3H); MS d .2 362

(M+, 10). Anal. Calcd for C,&N,I: C, 53 .O6; H, 4.1 7; N, 7.73. Found: C, 53 -36; H, 4.10;

N, 7.56.

4,SDipentyIphthaIonitrile (142). 4,5-Di(I-pen~yl)phthalonitriIe (135) and 50 mg of Pd

on BaSO, catalyst (Aldrich) were added to a Parr hydrogenation bottle containhg 500 rnL

of 100% ethanol. The bottle was installeci in a Parr-shaker apparatus and pressurized to 36

psi. Mer 24 h, the bonle was taken off and the solid catalyst was rernoved by simple

filtration. The solution was preabsorbed on a smdl amount of classical silica gel, Ioaded on

a column containing silica gel of the same grade, and eluted with hexane and ethyl acetate

(955) . The first few fiactions were combineci and the solvent evaporated to yield a yellow

oil. The oil was dissolved in a srnail amount of hexane and left to aystaliize (at - 10 O C for 4

h). The supernatant hexane was decanted and 83 mg of the white crystalline solid, 43-

dipentylphthalonitrile (142) was recovered in 80.5% yield: mp 41-43 OC;

'H NMR (CH,CN) G 7.70 (s, 2H), 2.68 (t, J = 7.8 Hz, 4H), 1.93 (m, 4H), 1.56 (m, 4H), 1.33

(m. 4H), 0.90 (t, J = 4 Hz, 6H); IR (Dr) 2230 (CN) c d ; MS m/s 268 (hl+, 85). And.

Cdcd for C,,H&: C, 80.59; H, 8.95; N, 10.45. Found: C., 80.33; H, 9.23; N, 10.24.

4J-Di(3J-dimethyibu tyi)phthaionitrile (143). To 1.44 g (5 mrnol) of 136 dissolved in

150 mL of absolute etbanol and was added 0.5 g of palladium on barhm d a t e d y s t .

The reaction mixture was placed in a P m hydrogenation bottle, and the bottle was installeci

in a Parr-Shaker apparatus and pressurized to 36 psi. After 2 h the reaction was complete,

the catalyst was filtered and the solvent was evaporated. The residue was pinified by

column chromatography using ethyl acetate and hexane (1:9) as eluent. The f h t few

fhctions, containing the desired product, were combineci and rotary evaporated to yield

white crystals. Recrystallization h m hexane gave us 1.25 g of pure 4,543.3-

dimethylbu~l)phthalonitrile (143) in 85% yield as white crystais: mp 127-129 O C : IR (KBr)

2235 (CN) cm-'; 'H NMR (400 MHz, CDCl3) 6 7.56 (s, 2H). 266 (m, 4H). 1.44 (m, 4H).

1 .O2 (s, 18H); MS m/z, 296 (MJI+, 82). Anal. Calcd for C&ZSNZ: C, 8 1 .O3; H, 9.52; N, 9.45.

Found: C, 81.28; H, 9.51; N, 9.46.

3,4-Di(3J-dimethyl-1-butyny1)phthaIonitriie (150) and 3-bromo4(3 J-dimethyC1-

butyny1)phthalonitrile (152). To 10 mL of a triethylamine/DMF (1 : 1) solution

containing 210 mg (0.73 mol) of 3.4-dibrornophthalonitnle (123). was added 0.4 mL of

3,3-dhethyl-1-butyne, 100 mg of cuprous iodide, and 10 mg of Pd[P(Ph,),],Cl, as a

catalyst. The mixture was stirred at a room temperature under an argon atrnosphere.

M e r 18 hours, the starting material disappeared and two products appeared as shown by

a thin layer chromatogram. Although an additional three portions of 3.3-dimethyl-1-

butyne, cuprous iodide, and Pd(I1) catalyst were added to the reaction mixîure every 8

butyne, cuprous iodide, and P d 0 catalyst were added to the reaction mixture every 8

hours, the reaction did not proceed further. The reaction mixture was £iltered to remove

insoluble solids and the solids were washed with ethyl ether until the washings did not

show any spot on TLC. The filtrate and the washings were combineci together and the

solvent was evaporated under 2 reduced pressme to give 70 mg of dark brown solids.

The mixture was preabsorbed on silica gel and chromatographed over silica gel ushg

hexane/ethyl acetate (19: 1) as eluent to give, in the first fkctions, in 40% yield, 85 mg of

3,4-di(3,3-dimethyl- 1 -butynyl)phthalonitxile (1 50) as white crystals; mp 147- 149 O C : IR

(KBr) 2235 (CN) cm*'; 'H NMIZ (400 MHz, DMSO-d6) 6 8.00 (d, 1 H, J = 8 Hz), 7.85 (d,

lH, J = 8 Hz), 1.36 (s, 9H), 1.34 (s, 9H), MS mlz, 288 (hlf, 80). Anal. Calcd for CZJ12&:

C, 83.28; H, 7.00; N, 9.71. Found: C, 83.1 1; H, 7.14; N, 9.69.

Further elution gave 95 mg 3-brorno4(3,3-dimethyI-l-bufynyl)phthalonitriIe (152) in 45%

yield; mp 139- 140 OC: IR (KBr) 2230 (CN) cm-'; 'H NMR (400 MHz, DMSO-d6) 6 d 8.10

(d, lH, J = 8 Hz), 7.92 (d, lH, J = 8 Hz), 1.35 (s, 9H), MS m/z, 286,288 (M+, 100%).

Anal. Calcd for C,,H,,N,Br: C, 58.15; H, 3.83; N, 9.69. Found: C, 58.65; H, 3.74; N, 9.70.

1,2,8,9,15,16~2J3-0cta(3~-dimethy~-1-bu~y1)ph~~ocy~he (153). The same

method as dacribed above for 141 using 50 mg of 150 in 0.5 mL of 1-pentanol gave 17 mg

of 136 in 35% yield: 'H NMR (400 MHz, nitrobemene-d, 2.44 x IO", 1 17 OC) 6 9.70 (ci, J

= 7 Hz, 4H), 8.45 (d, J = 7 Hz, 4H), 1.79 (s, 36H), 1.72 (s, 36H), -0.16 (br, 2H); UV-vis L

max (CHClJ (log e) 734 (5.32), 698 (5.27), 666 (4.72), 632 (4.59), 418 (4.65), 368 (5.03),

314 (4.89) nm; FAB MS (M+1, 1154). Anal. Calcd for Ca8&: C, 83.15; Hl 7.15; N,

9.70. Found: C, 83.10; H, 6.79; N, 9.09.

lJ-Bis-2'-(9',1 Oq,l 6',l7', 23'J4'-he~akis(3"~~-dhethyl-ln-

butynyl)phthalocy~noxy~2-ethyl-2-methylpropne (1 54). To a suspension of 0.1 mol

of lithium 1-pentoxide in 10 mL of 1-pentanol was added a mixture of 1.6 g (5.4 mmol)

of 136 and 100 mg (0.27 m o l ) of 1,3-bis(3,4-dicyanophenoxy)-2-ethyl-2-

methylpropane (73c) which had been preliminary well ground together. The mixture was

stirred at 100 O C for 4 hours under an argon atmosphere. Mer the mixture was cooled to

room temperature, the reaction was quenched by the addition of methanol, concentrated

hydrochloric acid, and ethanol(1: 1 : 1). The blue precipitation obtained in this way was

collected by filtration with suction and was successively washed with acetonitrile until

the washuigs huned almost colourless. The remaining solids (1.5 g) were dissolved into

toluene and then chromatographed over silica gel (toluene) to remove impurities which

stuck to the silica gel. This procedure was repeated twice. Mer the solvent was

evaporated, the desired binuclear phthalocyanine was extracteci nom the solids with four

portions of 10 rnL of THF. The remained solids (1.3 g) were almost pure mononuclear

phthalocyanine 141. Removai of the solvent of the extract under reduced pressure gave

100 mg of solids. This was dissolved into THF and chromatographed over SX-4 GPC gel

using THF as an eluent. Polynuclear Pcs, the desired binuclear 154, and then

mononuclear 141 phthdocyanines were eluted out in this order. The fkactions containing

the second band were collected and the solvent was evaporated under reduced p-.

The remaining solids (50 mg) were f.urther purifiai by flash column chromatogrirphy to

remove 141. A small amount of 141 eluted out with hexandtoluene (1 : 1) and then 154

was eluted with hexaneltoluene (1 :3). The fiactions containhg the second band were

collected and the solvent was vaporized out under a reduced pressure. The solids

obtained in this way were recrystallized fiom chlorofodacetonitrile ht, and then h m

THF/ethanol, and then washed with ethanol, and dried in vacuum at 80 O C . A 20 mg

sample of the blue powders of 154 was obtained in this way (yield, 3.5 %). FAB-MS m/z

2104 (M+) (the exact molecular weight is 2104.8); 'H NMR (400 MHz, benzene-d,, 9.44 x

IO', 57 O C ) 6 9.49 (s, 2H), 9.46 (s, 2H), 9.00 (s, 2H), 8.92 (s, 2H), 8.88 (s, 2H), 8.32 (s, 2K),

8.24 (d, 2H), 7.69 (m, 2H), 7.50 (ci, 2H), 4.30 (m, 4H), 1.82 (s, l8H), 1.76 (s, 18H), 1.72 (s,

18H), 1.71 (s, 18H), 1.64 (s, 18H), 1.61 (s, 18H), 1.18 (s, 3K), 1.10 (t, 2H), -1.65 (br,4H);

W-vis (benzene) &, (THF) (log e): 698 (4.98), 400sh (ca. 4.6), 364 (4.91), 3 10 (4.84)

nrn. Anal. Calcd. for C,,,H,,N,,O,: C, 81 .O3; H, 6.80; N, 10.65. Found: C, 81 . l5; H,

6.78; N, 10.53.

Bi~(7~,8~12~,13~,1 7~182-hexakis(3t,3'-dimethyCl '-butynyl)benzo[g,l,q]-5,I O,l5,2O-

tetraazaporphyrin yl) [b,q benzeae (1 55). To a suspension of 0.1 mol of lithium 1 -

pentoxide in 10 mL of 1-pentanol was added a mixture of 2.0 g (7.0 m o l ) of 136 and

100 mg (0.56 mmol) of 1,2,4,5-tetracyanobenzene (50) which had been preliminary well

ground altogether. The mixture was s h e d at 135 O C for 1.5 houn under an argon

atrnosphere. After the mixture was cooled to room temperature, the reaction was

quenched by the addition of methanol, concentrated hydrochlonc acid and water. The

blue precipitation obtained in this way was coliected by filtration with suction and was

successively washed with acetonitrile until the washings tumed almost wlourless. The

residual solid was extracteci 5 times with benzene and then chromatographed over silica

gel using benzene as eluate. The chromatography was repeated three times using a

benzene/hexane (1 : 1) mixture as eluent to remove less soluble impurities. The h t

fractions consistai of a mixture of mononuclear phthalocyanine 141 and the desired

binuclear phthalocy anine 1 55. The later fiactions were composed mostly of mononuclear

Pc 141. The fiactions with compound 155 were collected and two phthdocyanines were

separated using GPC on SX, (CHCI,). The f h t fkctions consisting of binuclear Pc 155

were isolated and the desued compound 155 was M e r purified using flash column

chrornatography on silica gel. An 18 mg sample of 155 (1 3%) was isolated this way as a

green-gray powder: 'H NMR (400 MHz, benzene-d, ,2.6 x 104; 27 OC) 8 1 1.29 (S. 2H),

9.66 (s, 4H), 9.30 (s, 4H), 9.10 (s, 4H), 1.98 (s, 36H), 1.89 (s, 36H), 1.79 (s, 36H), -2.32 (br,

4H); UV-vis &, (O-dichlorobenzene) 935 ,885,788,728,662 nm; FAB MS (M+l,

1912).

1,8-Bis(2'J'-dicyanopheny1)naphthalene (157). To a solution of 254 mg (1 mmol) of

3-iodophthalonitde (12a) in 2 rnL of 1,3-hethyl-3,4,5,6-tet~ahydro-2(1 l3)pyrimidinone

was added 150 mg of zinc powder and the resulting mixture was heated at 45-50 O C for 5

h in an ultmonic cleaner under argon (colour changed h m yellow to rd) . The resulting

mixture was moved to a heated (50 O C ) oil bath, and the mixture of 190 mg (0.5 mmol) of

1,8-diiodonaphthalene (90) and 15 mg of Pd(PPh,), were added. The reaction mixture

then was stirred for an additional 5 h at 50 O C and then diluted with 50 mL of benzene,

filtered fiom unreacted zinc powder, extracted thrice with water and d r id over anhydrous

MgSO,. The solution was concentraiecl to 1 0 mL and then chromatographed over silica

gel using benzene as eluate. The first hctions consisted of products of decomposition of

the catalyst and a trace of 1 -iodo-8-(2',3'-dicyanophenyl)naphthalene. The later fiactions

were composed mostly of 157 with some phthdonitrile as a product of deiodination.

Additional chromatographie purification and recrystallization fiom benzene afEorded 95

mg of 157 (50%) as gray-yellow crystals; mp 317-319 OC: IR (KBr) 2235 (CN) cm-', 'H

NMR (400 MHz, DMSO-d,, 57 OC) 6 8.30 (d, 2H, J = 6.6 Hz), 8.22 (d, 2H, J = 7.7 HZ),

8.19 (d, 2H), 8.17 (4 2H) (these two doublets appears as triplet), 8.00 (t, 2H, J = 7.9 Hz),

7.88 (d, 2H, J = 7.9 Hz), 7.69 (t, 2H, J = 7.8 Hz), 7.61 (d, 2H, J = 6.6 Hz), 7.31 (t, ZH, J =

7.5 Hz), MS mlz, 380 (M+, 100).

1,S-Diaminoanthraquinone (161). The procedure of House [IO21 was used to prepare

compound 161: mp 266-268 O C (lit. [IO21 mp 265-268 OC).

1,8-Diaminoanthracene (163). To a suspension of 1 g (4.2 rnmol) of 161 in 175 mL of

isopropanol was added 0.9 g (24 m o l , 5.8 equiv.) of NaBH,. M e r the mixture had

been refluxed for 2.5 h, an additional 0.45 g (12 mmol, 2.9 equiv.) of NaBH, was dded

and reflux conditions were continueci for 3 h. The solvent was evaporated and the

resulting solid was extracted five times with ethyl acetate. The resulting mixture was

pfeabsorbed on silica gel and then chromatographed using a mixture of

benzene/acetonitrile as eluate. When benzene was used as an eluate fkactions with

unreacted starting material 161 and 1,8diamino-9,l O-dihydroanthraquinone 162a were

collected Mer changing the eluate to a mixture of benzene/acetonitrile (4: 1) h t i o n s

with, what we suggest, is the very unstable intermediate l,8-diamino-9,1 O-

dihydroanthracene (162b) were collected [102]. Further elution with a

benzene/acetonitrile (1 : 1 ) mixture gave us 2.0 g (46%) of 1,8-diaminoanthracene (1 63),

mp 177-179 OC: 1R P r ) 3430 (NH) cm-': 'H NMR (400 MHz, CDCI,, 27 OC) 6 8.78 (s,

lH), 8.17 (s, lm, 7.22 (m, 4 3 9 6.62 (d, 2H, J = 7 Hz), 5.56 @s, 4H), MS mlr, 208 (M+,

85). Anal. Calcd. for C,,H,,N,: C, 80.73; H, 5.82; N, 13.45. Fond: C, 80.6 1; H, 5.75; N,

13 .OO.

l,8-Düodoanthracene (164). A suspension of 1.5 g of 163 (7.2 rnmol) in a mixture of 8

mL of concentrated sulfunc acid, 10 mL of water and 23 g of ice was cooled to -20 O C

and then a solution of 2.6 g of NaNO, in 11 mL of water was added, dropwise and with

stimng, while the temperature of the mixture was kept at -15 to -20 OC. As soon as the

addition was complete a solution of 10 g of KI in 13.5 mL of water was added, dropwise

with stimng . During thi s addition the reaction mixture was kept a? - 1 5 to -20 OC and

additional portions of concentrated sulfunc acid were added as needed to keep the

reaction mixture h m freezing. The reaction mixture was wanned to 80 OC, rapidly and

with stirring, and then cooled to 20 OC and made alkaline by the addition of solid NaOH.

The mixture was filtered and the black solid residue was colîected and extractecl with

several portions of boiling diethyl ether. The solution was washed with 10% HCl,

sahirateci aqueous N+S,O, and then dried over MgSO,. Solvent was evaporated and the

residue solid was chromatographed over silica gel using benzene as eluate. The first

fkactions, consisting of the desired product, were evaporated and the solid was

recrystallized fiom benzene to give 1.4 g (45%) of 1,8-diiodoanthracene (164), mp 207-

210 OC: 'H NMR (400 MHz, CDCl,, 27 OC) 6 8.97 (s, lH), 8.33 (s, IH), 8.17 (d, 2H, J =

Tl), 8.02 (d, 2H, J=8.2Hz), 7.21 (t, 2H, J=%8),MSm/z,430(~+,65).

CONCLUSION

We have developed a reliable synthesis of 4,5-diiodophthaionitrile (117a) h m

phthalimide (1 13). The effêct of temperature on the yield of 1 l7a was detennined. The

by-products of the reaction were isolated and characterized. The new 3,4-

diiodophthaloniûile (1 17b) is the first example of a 3,4-disubstituted phthalonitrile.

Phthalonitrile Il7a has excellent properties necessary for use as a starthg material for the

synthesis of 4,5-disubstituted phthalonitriles. It can be easily synthesized nom

phthdimide in large quantities and two iodine substituents in this compound are very

reactive toward substitution. The structure of 1 l'la was proved by synthesis and

characterization of 4-iodo-5-(1-octyny1)phthalonitrile (149).

In this research convenient methods of synthesis of brominated phthalonitriles were

developed. Direct bromination of phthalonitrile (3) using N,N-dibromoisocyanuric acid

(120) in sulfunc acid was closely examined ushg HPLC. The dependence of the yields of

the brominated phthalonitriles on reaction t h e and sulfunc acid concentration was

investigated. Five bromosubstituted phthalonitdes, namely, 3-bromophthalonitnle ( l t l ) ,

4-bromophthalonitrile (13), 3,6-, 3 4 - and 4,s-dibromophthalonitriles (1 22,123, 124)

were isolated f?om the reaction mixture and cornpletely characterized, including four new

compounds 121 -1 24. A non-separable mixture of another two bromosubstituted

phthalonitriles was isolated and investigated. Pathways of bromination were investigated

utilizing HPLC and using bromosubstituted phthalonitriles as starting materiais.

Convenient methods of synthesis and separation for monosubstituted and disubstituted

bromophthalonitrile were developed. New methods were developed for the synthesis of

3-bromophttialoni~les (121) fiom 3-nitrophthdonitrile (6a) and 4,s-

dibromophthalonitrile (124) h m phthalimide (113). Phthdonitrile 124 was proposed as

an excellent starting matenal for the synthesis of 4,s-disubstituted phthdonitriles which

on further condensation yielded single isorner octasubstituted Pcs.

The possibilities of direct bromination of substituted phthalonitriles were investigated and

4-hydroxyphthaloniûile (7b) was selected as a starting matenal. New phthaloniûiles 3,s-

dibromo4hydroxyphthalonihile (130a), and, as an inseparable mixture, 4-bromo-5-

hydroxyphthalonitrile (130b) and 3-bromo4hydroxyphthalonitriIe (130c) were isolated

and characterized by 'H NMR. Compound 130a was completely characterized and

ablation with l-brornobutane of 130b and 130c was carried out using the Williamson

substitution method. 4-Bromo-S-butoxyphthalonitile (13 1 a) and 3-bromo4-

butoxyphthalonitrile (131 b) were isolated and completely characterized.

Five new 4,5-diallçynylphthalonitnles 132-1 36 were synthesized fiom 1 17a and 12 4 and

l-alkynes using three different methods. Some of these phthaloniûiles were condensed to

2,3,9,lO, 16,17,23,24-octaaUcynylphthalocyanines and their zinc derivatives. All of the

octaailqnyl Pcs were very soluble in organic solvents especially the metal fiee and zinc

derivative of Pcs with 3,3-dimethyl- 1-butynyl substituents 141 and 148. The UV-vis

spectra of these compounds were very similar, and it was found that one alkynyl group

causes a red shift of the Q band by 4-5 nrn at 700 nm. The importance of this fact is that

the absorption maximum of the Q-band cm be "tuned" depending upon how many allcyne

substituents are present. 'H NMR studies of these Pcs at dinerent concentrations and

temperatures clearly demonstrate the importance of quoting concentration and

temperature values when reporting 'H NMR spectra of phthalocyanines. The

aggregational phenornena between phthalocyanines moieties was discussed and believed

to be the main cause of the downfield chemical shifi of intemal and aromatic protons with

increasing the temperature or with decreasing the concentration of Pc in solution. In

attempts to determine the tnie chernical shifts of the aromatic protons of zinc derivatives

of the octaakynyl Pcs the 'H NMR spectra of diflerent ratio mixtures of ZnPc 148 and

p y d n e were studied. As expected, a downfield chemical shift of the aromatic protons of

148 was observed with an increase of the concentration of pyrazine in solution. At the

same time, with decreasing the pyrazine/l48 ratio the chemical shift of the pyrazine

protons was shifted more than 2.2 ppm upfield fbm 8.0 pprn for the pure compound to

5.8 ppm for the 1 :2 mixture.

3,4-Dibromophthalonitnle (1 17b) and 3,4-diiodophthalonitrile (1 2 3) were investigated as

precursors for the synthesis of 3,4di(3,3-dimethyl-l-butynS)phthdoni~Ie (150). This

cornpound is the f k t example of a 3,4disubstituted phthalonitrile that was synthesized.

The reaction conditions were studied and the by-products of this reaction were

investigated and characterized. The condensation of 150 under the same conditions as for

the 2,3,9,lO, l6,l~,Z~,~~octaal@nylphthalocyanines led to the formation of the single

isomer, 1,2,8,9,15,16,22,23-octa(3,3-dimethyl-l-butynyl)phthal0~yanine (1 53). This new

compound was wmpletely characterized and 'H NMR study showed the same

dependence of chernical shifts of intemal protons by the temperature, as for the

2,3,9,lO, 16,17,23,24-octasubstituted Pcs.

Hydrogenation of the triple bonds in phthalonitriles 135 and 136 using cataiytic reduction

with hydrogen employing a palladium catalyst on carbon produced dialkylphthalontriles.

Two phthalonitriles were synthesized in this way: 4,5-dipentylphthalonitnle 142 and 43-

di(3,3 -dimethylbutyl)phthalonitnle (1 43). Although syntheses of 4,s-

diallcylphthalonitnles were previously developed, our method of preparation gives higher

yields and does not include the high temperature reaction of replacement of bromine (or

iodine) in the aromatic ring with cyan0 groups using CuCN.

From d l newly synthesized phthalonitriles, 136 was the most soluble and most easily

crystallized compound. Phthalocyanine 141, the product of self condensation of 136, was

one of the most soluble Pcs in organic solvents and the eight 3,3-dimethyl-1-butynyl

groups in phthalocyanine 141 were excellent for prevention of aggregation between Pcs.

It was very soluble in benzene, chloroform and THF, and even moderately soluble in

hexane . Employing its unique properties we used phthdonitrile 136 for the formation of

binuclear Pcs.

A new single isomer binuclear 1,3-bi~-2~-(9', 1 O', 16', 1 7',23',24'-hexakis(3 n,3"-dimethyl- 1 "-

butyny1)phthalocyaninoxy)-2-ethyl-2-methylpropane (154) was synthesized in 3.5% yield

fiom 1,3-bis-(3',4'-dicyanophenoxy)-2-ethyl-2-eylprope (73c) and 136. Although

binuclear Pc 154 was less soluble than mononuclear Pc 141, it was moderately soluble in

benzene and other organic solvents, chloroform, and THF. Good solubility and its

relatively simple structure, compared to other binuclear Pcs (which existed as a mixture

of isomers), allowed us to do temperature and concentration studies by NMR

spectroscopy. Unusual dependence of the chernical shifts of the aromatic and intemal

protons of 154 on changes in temperature led us to propose two kinds of interactions of

the Pc macrorings in the molecule. Intermolecular interaction between Pc rings of

different molecules were weaker then intramolecular interaction between two Pc aromatic

rings of the same molecule. Increasing the temperature, at which 'H NMR spectra were

accomplished, allowed us to interpret al1 signds in the spectra including six singlets for

aromatic protons and six singlets for the non identical CH, groups of Pc 154.

Another binuclear Pc was synthesized fiom tetracyanobenzme (50) and 136. Although

this kind of binuclear phthdocyanines was synthesized before, newly synthesized

bi~(7~,8', 12', 1 32, 17', 1 82-hexakis(3',3'-dimethyl-1'-butynyl)benzo[g,l,~-5, 10,15,2O-

tetraazaporphyrinyl) [b,flbenzene (155) had many unique properties. First of al1 because

of its hi& solubility in organic solvents (for example, in beozene or chloroform it was

more soluble than 141) we were able to assign al1 'H NMR proton signals of this

compound. The extensive n-system of the two phthalocyanine rings sharing one benzene

ring of 155 was expandecl by twelve triple bonds. The W-vis spectnim of 155 was very

u n d even for binuclear Pcs. The Q-band of this compound was shifted into the low

energy spectrum. A quite broad absorption band was observed in the 600-800 nm region

with an absorption maximum at 788 nm and 810 nm and two shoulden at 662,728.

Unfomuiately, binuclear Pc 155 was a very unstable compound. Themial decomposition

of 155 was observed using 'H NMR and UV-vis-IR spectra.

Attempt to synthesize a binuclear Pc with an aromatic bridge resolved into the synthesis

of 1,8-bis(2,3-dicyanopheny1)naphthalene (1 57) and 1,8-diiodoanthracene (1 64). A 'H

NMR study of bisphthaloniûile 157 showed that this compound exists as two rotamers

with a very high energy of interconversion, that cannot be observed even at the maximum

operating temperature of 154 OC of our NMR instrument. A five step synthesis of 164

fiom 1,8-dichloroanthraquinone (160) was the final part of this research. Two new

compounds were synthesized at this stage: 164 and 1,8-diaminoanthracene (163).

The main achievernent of this research is an investigation of convenient synthetic routes

of preparation of differently substituted bromo- and iodophthalonitriles. These

phthdonitriles were used as precursors for the synthesis of unusual dialkynyl

phthalonitriles and single isomer mononuclear and binuclear akynytphthaiocyanines.

Exceptional solubiiity and simple 'H NMR allowed us analyze temperature and

concentration dependence of the 'H NMR shifts of aromatic and intemal protons of these

Pcs.

C. C. Lemoff and A. B. P. Lever Eds, "Phthalocyanines: Properties and

Applications ", Vol. 1-4, VCH Publishm Inc., New York (1 989, 1992, 1993, 1996)

H. Moser and L. Thomas, "The Phthdocyanines ", Vol. 12, CRC Press Inc., Boca

Raton, Florida 1983.

K. Kasuga and M. Tsutui, Courd Chem. Rev. 32,67 (1980). A. B. P. Lever, A&.

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