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This is to certify that the

thesis entitled

SYNTHESES OF PORPHYCENE
AND N,N'-BRIDGED PORPHYCENES

presented by

Irene M. Morrison

has been accepted towards fulfillment
of the requirements for

MMTW degree in _C Lem}

(24 [a a

Major professor :2;

MS U is an Affirmative Action/Equal Opportunity Institution

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MSU le An Mmeflve AcfloNEquel Opportunity Inetltwon
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SYNTHESES OF PORPHYCENE
AND N,N'—BRIDGED PORPHYCENES

By

Irene M. Morrison

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Chemistry

1 994

ABSTRACT

SYNTHESES OF PORPHYCENE
AND N,N'-BRIDGED PORPHYCENES

By

Irene M. Morrison

The formation of a one-carbon bridge between pyrrolic nitrogen
atoms of porphycene, forming a seven-membered ring in a bicyclic
compound, was achieved by using DMF/POC13 in Vilsmeier—type reaction
conditions. N,N'-Bridging was also accomplished by using N-
methylforrnanilide in 1,2-dichloroethane/POC13, and 3-(dimethylamino)-
acrolein in l,2-dichloroethane/POC13 affording N,N'-((N,N-dimethyl-
amino)methylene)-2,7,12,17-tetrapropy1porphycene, N,N'-((N-methyl-
aniline)methylene)-2,7,12,l7-tetrapropylporphycene, and N,N'-(C-C=C-
NMe2)-2,7,12,17-tetrapropylporphycene, respectively. N,N'-((N-methyl-
amino)methylene)-2,7,12,17-tetrapropylporphycene was characterized by
NMR and x-ray crystallography. Synythesis of 2,7,12,17-tetrapropyl-
porphycene was also optimized to provide a higher yield of this rather

difficult-to-obtain macrocycle.

This is dedicated to the memory of Tom Morrison, who was my inspiration

for this work.

ACKNOWLEDGEMENTS

I would like to thank Professor C. K. Chang for his direction,
patience and financial support during the course of this work. Financial
support from the chemistry department and Michigan State University in
the form of fellowships and teaching assistantships is also gratefully
acknowledged.

I would also like to thank Professors G. L. Baker and T. J. Pinnavaia
for serving as members of my guidance committee.

Past and present members of our group deserve special thanks for
their friendship, encouragement and helpful discussions.

Thanks also go to Kermit Johnson, whose help with the 15N NMR
data collection is most appreciated.

Finally I would like to express my thanks to my family and dear

friends for their understanding, encouragement and love.

iv

TABLE OF CONTENTS

List of Figures ......................................... vi
List of Abbreviations ..................................... vii
Introduction ........................................... 1
Results and Discussion .................................... 7
Experimental .......................................... 25
Future Work .......................................... 36
List of References ....................................... 39

Figure 1.

Figure 2.
Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

LIST OF FIGURES

N -N' Distances in porphycene and porphyrin ............ 3
Synthesis of iodopyrrole 8 ......................... 8
Synthesis of 2,7 ,12,17-tetrapropylporphycene 12 ......... 9

UV/Visible spectrum of 2,7,12,17-
tetrapropylporphycene 12 ........................ 12

15N NMR of 15N-2,7,12,17-tetrapropylporphycene
at 30° C and 0° C ............................... 14

Synthesis of N ,N'-((N,N-dimethylamino)methylene)-
2,7 , l 2,17-tetrapropylporphycene l3 .................. 15

1H NMR spectrum of N,N'-((N,N-dimethylamino)-
methylene)-2,7,12,17-tetrapropylporphycene l3. ......... 17

UV/Visible spectrum of N,N'-((N,N-dimethylamino)-
methylene)-2,7,12,17-tetrapropylporphycene 13 .......... 18

X-Ray crystallographic structure of N,N'-((N-methylamino)-
methylene)-2,7 ,12,17-tetrapropy1porphycene 1 4 ......... 19

Figure 10. Synthesis of N,N'-((N-methylaniline)methylene-

2,7,12,17 -tetrapropylporphycene 15 ................. 21

Figure 11. UV/Visible spectrum of N,N'—((N-methylaniline)-

methylene)-2,7,12,17-tetrapropylporphycene 15 ....... 21

Figure 12. 1H NMR spectrum of N,N‘-((N-methylaniline)-

methylene)-2,7,12,17-tetrapropylporphycene 15 ........ 23

Figure 13. Synthesis of N,N'-(C-C=C-NMe2)-2,7,12,17-

tetrapropylporphycene l6 ........................ 22

vi

Figure 14. UV/Visible spectrum of N,N'-(C-C=C=NMez)-
2,7 ,12,17-tetrapropylporphycene l6 ............... 24

Figure 15. Synthesis of N,N'-((rnorpholine)methylene)-
2,7,12,17-tetrapropylporphycene l7 ................ 36

Figure 16. Synthesis of N-alkoxy-2,7,12,l7-
tetrapropylporphycene 18 ........................ 37

Figure 17. Synthesis of 2,7,12,17-tetrapropylporphycene dimer
with piperazine connector ....................... 38

vii

DCI
FAB
OEP
PDT
Rf

RT
TEBA

TLC
TPP
TPPc

LIST OF ABBREVIATIONS

Desorption chemical ionization
Fast atom bombardment
Octaethylporphyrin
Photodynamic therapy
Retardation factor

Room temperature
Triethylbenzylammonium chloride
T etrahydrofuran

Thin layer chromatography
Tetraphenylporphyrin
Tetrapropylporphycene

INTRODUCTION

Although the concept of a light-activated sensitizer resulting in cell
death was first used to treat cancer in 1903,1 it is only recently that
photodynamic therapy (PDT) has been investigated on a large scale. The
exact mechanisms of action for effective PDT in cancer treatment are not
known. Studies with animal models have indicated that generation of
singlet oxygen is the main mechanism for PDT cytotoxicity producing
vascular damage to the blood vessels of the tumor resulting in tumor
hypoxia and cytotoxicity.;3

PDT is an oxygen-dependent photochemical oxidative process which
requires three simultaneously present components for cytotoxicity: a
sensitizer, light and oxygen. The sensitizer must localize in tumors and
have photodynamic properties that, when activated by light, lead to
cytotoxicity. The most widely used sensitizers in clinical studies have been
porphyrin-based photosensitizers, which are preferentially absorbed and
retained by cancerous tissues. Why the sensitizer is retained to a greater
extent in tumors than in normal tissues is unknown, however, the
distribution of different porphyrin-based sensitizers is determined by the
individual chemical properties, including lipophilicity or hydrophilicity,
polarity, pH, anionic or cationic charge, and aggregate size.4 Since
porphyrins in general have weak absorption at 630 nm, the wavelength

usually used for treatment, it is desirable to develop photosensitizers with

2
strong absorption at longer wavelengths. The absorption at longer

wavelengths allows greater tissue penetration by low energy light and
prevents the problems associated with light absorbance by naturally present
biologic chromophores such as hemoglobin.5

A compound currently under study as a photosensitizer with strong
absorption at longer wavelengths is porphycene 1. Since 1990 Vogel has
been granted two US. patents and applied for two international patents6

for porphycene-based compounds useful in PDT.

Porphycene is an aromatic tetrapyrrolic macrocycle resembling
porphyrin 2 in chemical, structural and spectral respects. This structural
isomer of porphyrin is derived by merely shuffling the pyrrole and
methine moieties.

Porphycene was first synthesized7 and characterized in 1986 by
Vogel. It is stable in air, crystallizes in the form of violet needles, and is
soluble in organic solvents to give blue solutions showing red-violet
fluorescence. The name "porphycene" was suggested for 1 because the
compound possesses structural features of both porphyrins and acenes.

The spectra7 of the compound provide convincing evidence as to its

structure and aromaticity. The simplicity of the 1H and 13C NMR spectra

3
as reported by Vogel indicate the equivalence of the four pyrrole rings

which is readily explained by assuming that porphycene, like many
porphyrins, is subject to NH tautomerism that is rapid on the NMR
timescale. The NH signal of porphycene (6 3.15) is significantly less
shifted to high field, relative to that of pyrrole (8 7.70), than is that of
porphyrin (6 -3.76). This is suggestive of strong intramolecular N-HmN
hydrogen bonding in porphycene, which is expected if the molecule is
planar. The mass spectrum also confirms the structure with the molecular
ion, m/e 310, as the base peak. An x-ray crystallographic analysis showed
the molecule to be virtually planar, with a maximum distance of C and N
atoms from the mean plane: i 0.04 A. It also showed that the cavity
between the pyrrole rings in porphycene is smaller that that in porphyrin.

In porphycene the four nitrogen atoms form a rectangle, the sides of which

 

porphycene porphyrin

Figure 1. N-N' Distances in porphycene and porphyrin.

are 2.83 A (N 1N2) and 2.63 A (NINI') long compared to porphyrin's NN'
distance of 2.89 A (Figure 1). This finding further supports the strong

4
hydrogen bonding evidenced by the NMR spectrum. The uv/visible

spectrum of porphycene consists of a double band at k = 358/370 nm,
which is a Soret band, and three longer wavelength bands at l = 558, 596,
and 630 nm, which are the Q-bands. This finding supports the porphyrin-
like nature of the compound, however, porphycene shows higher
absorption for the Q-bands. It is this finding along with porphycene's
stability toward photooxidation, high quantum yield of fluorescence and
singlet oxygen sensitization,3 that suggest that this novel porphyrinoid and

its alkyl derivatives are potential agents for PDT.

N,N' One-carbon bridged porphyrins were first synthesized by
Johnson et al.9 in 1975 by the condensation of ethyl diazoacetate with cobalt
porphyrins giving a salt, which by the action of acid under oxidative
conditions, was converted to 21,22-ethoxycarbonylmethyleneoctaethyl-
porphyrin with removal of the metal. When synthesized from Co(II)
octaethylporphyrin (OEP), rather stable N,N' bridged porphyrins were
formed with a yield of 51.9% from the intermediate salt. When
synthesized from tetraphenylporphyrin (TPP), the reaction was slower
with a much lower yield (3%), and the bridged compounds were less stable
probably due to steric interaction between the meso-phenyl and the
ethoxycarbonylmethylene fragment. Hot solvents easily decomposed the
TPP-bridged compounds back to TPP.

A series of N,N'-bridged porphyrins were synthesized in 1982 by
Callot et al.10 using TPP with chloroform and base under phase transfer
conditions (NaOH, H20, ROH, TEBA), giving yields ranging from 16-
25%. Under the same conditions, OEP gave a low yield (5.5%) of bridged
porphyrin, which is a reversal of Johnson's studies using OEP and TPP.

The purpose of this study was to improve the synthesis of a soluble
and symmetric porphycene, 2,7,12,17-tetrapropylporphycene (TPPc), and
to use it as the parent compound to further synthesize other N-alkylated
porphycenes, in an attempt to develop new sensitizers useful for PDT.

N-Alkyl porphycenes, by their similarity to N-alkyl porphyrins,
should be compatible with living systems. N-Alkylated porphyrins are
synthesized in nature by cytochrome P-450,11 and N-substituted porphyrins
are produced by hemoglobin and myoglobin from the interaction with
hydrazines in vivo and in vitro.12 And in the early 1980s it was discovered
that a metabolite of certain drugs was N-methylprotoporphyrin IX.13

Synthetically, N -alkylation of most non-meso-substituted and meso-
tetraaryl porphyrins, except where noted, can be effected by a number of
methods: 1) direct alkylation with a stoichiometric amount of the highly
reactive triflouromethanesulfonate in refluxing methylene chloride;14 2)
direct alkylation with a 100-fold excess of alkyl iodide with acetic acid in
refluxing xylene;15 3) direct alkylation with dimethylsulfate in refluxing
1,2-dichlorobenzene;16 4) formation of an acetoxy complex of zinc(II) by
heating with ethyldiazoacetate in chlorobenzene, followed by migration of
the acetoxy from the zinc atom to a nitrogen atom, acidic elimination of the
zinc atom, alkaline hydrolysis of the ester, and photochemical
decarboxylation by exposure to sunlight;17 and 5) decomposition of an
N,N'-bridged porphyrin intermediate by treatment with an alkyl iodide
followed by p-toluenesulfonic acid (acceptable yields are only obtained for
mesa-tetraarylporphyrins).10

Our attempts to alkylate the porphycene by the CH31 method,

however, was unsuccessful, presumably owing to the low basicity of the

6
nitrogen of porphycene (pKa=1.3) as compared with a typical porphyrin

(pKa=5.5).

When Cu(II) TPPc was treated with the Vilsmeier reagent
(DMF/POC13) instead of the expected formylation product(s), we obtained
a N,N'-bridged porphycene whose structure, as will be discussed later in
this thesis, was determined by NMR and x-ray crystallography. N ,N'-
Dialkylporphyrins are rare; N,N'-bridged compounds are even more
unusual. Some of the alkoxymethylene-bridged porphyrins of Callot et
(11.10 were reported being not very stable and have a tendency to cleave one
or both N—C bonds. Our N,N'-bridged porphycenes are very stable
presumably because of the closer N-N' distance.

This thesis presents first an improved synthesis of the 2,7,12,17-
tetrapropylporphycene, and then the synthesis and characterization of two

N,N'-bridged macrocycles derived from this porphycene.

RESULTS AND DISCUSSION

The synthesis of the parent porphycene is shown in Figures 2 and 3.
In the first step a saturated aqueous solution of sodium nitrite was added
dropwise to a cold solution of ethyl butyrylacetate in acetic acid, followed
by stirring for 2 hours at RT, resulting in the formation of oxime 4.

The condensation of pyrrole 6 was achieved by dropwise addition of
oxime 4 along with small portions of zinc powder to a well-stirred solution
of ethyl acetoacetate 5 in acetic acid, maintaining the reaction temperature
below 75° C. The reaction mixture was then heated to 90° C with stirring
for another hour, then poured over ice water to precipitate the fine light
yellow powdery product.

The (it-methyl of pyrrole 6 was oxidized to a-carboxylic acid by
dropwise addition of bromine, under nitrogen, to a cooled solution of
pyrrole 6 dissolved in formic acid, glacial acetic acid and acetic anhydride,
followed by dropwise addition of sulfuryl chloride with vigorous stirring,
maintaining the reaction temperature below 10° C. Hydrolysis was
accomplished by slow addition of water followed by treatment with sodium
bicarbonate in ethanol and acidic workup yielding light yellow-green
crystals, pyrrole 7.

Decarboxylation was accomplished by dissolving pyrrole 7 and
sodium bicarbonate in water and 1,2-dichloroethane and heating the

mixture. To the reaction mixture was added dropwise an aqueous solution

 

 

COzEt C
l \ 2) 50202, ’ H20 / \
H

Etozc N HCOZH, HOAc, Eto2C
(CH3CO)20

 

Figure 2. Synthesis of iodopyrrole 8.

COzEt COZEt

C02Et
2 Vii _,., M /\
EIOZC N I Dw EIOZC N N COZEI
H H H
8 9

 

 

W Phcoc1, DMF»
N N NaOH, H20

10

II:
:E.‘

 

TiCl4, Zn
THF, py

12

Figure 3. Synthesis of 2,7,12,17-tetrapropylporphycene 12.

10
of iodine and potassium iodide, followed by refluxing for one hour,
forming the iodopyrrole 8, as creamy white needles.

Using an Ullmann type reaction, coupling of iodopyrrole 8,
dissolved in N,N-dimethylformamide at RT to which freshly ground
copper bronze was added, afforded white needle-like crystals, bipyrrole 9.
It was found that activating the copper and freshly grinding it immediately
before use gave more consistent results and a slightly higher yield.

Hydrolysis and decarboxylation of bipyrrole 9 was accomplished in
one step by dissolving bipyrrole 9 in a solution of ethylene glycol, sodium
hydroxide and water and refluxing the reaction mixture for 24 hours under
nitrogen. The solution was cooled and poured into water forming
bipyrrole 10 as a fine bluish gray powder which precipitated out and was
filtered, washed and dried. This was an improvement over Vogel's 2-step
procedure13 in which hydrolysis occured in aqueous sodium hydroxide/
ethanol solution, then decarboxylation was accomplished by sublimation at
160° C in small batches, under reduced pressure. These two steps, under
best conditions, gave an overall yield of 77%. By using a higher boiling
point solvent (ethylene glycol), the one-step procedure gave a greatly
improved yield of 96%.

Using Vilsmeier type reaction conditions, bipyrrole 10 was dissolved
in warm, dry N,N-dimethylformamide under nitrogen and cooled.
Benzoyl chloride was added dropwise to the cooled solution with stirring.
The reaction mixture was heated at 100° C for 18 hours under nitrogen,
then cooled and poured into cold water. With stirring, 10% aqueous
sodium hydroxide solution was slowly added until gold precipitate formed
and the smell of amine was apparent and persistent. The precipitate was

collected on celite, washed with water, rinsed with a small amount of

11

methanol and dried. Bipyrrole 11 was extracted from the celite with hot
chloroform, and the filtrate was evaporated in vacuo. The product was
recrystallized as a greenish gold powder in methylene chloride/methanol
(2%). The Vilsmeier reaction typically uses phosphorous oxychloride to
generate a highly reactive POCl3/DMF reagent for the electrophilic
aromatic substitution. We assumed that because the bipyrrole 10 was very
electron-rich, the high reactivity of the reagent was not required. By
substituting benzoyl chloride, a milder reagent, we were able to reduce the
amount of dark tarry by-products typical of Vilsmeier reactions and
increase the yield by 5%.

The final step, the cyclization of bipyrrole 11 to 2,7,12,17-
tetrapropylporphycene 12, was accomplished by reductive coupling using a
modification of the McMurry coupling reaction. Under a nitrogen
atmosphere freshly activated zinc dust was suspended in dry THF with
stirring, and titanium tetrachloride was added dropwise. After the
exothermic addition was complete, the reaction mixture was heated to
reflux and refluxed for 15-20 minutes. Bipyrrole 11 was dissolved in dry
THF and pyridine and added dropwise to the gently refluxing titanium
mixture. The reaction mixture was refluxed for another hour, cooled,
quenched with an aqueous solution of potassium carbonate, and allowed to
sit for 36 hours at RT. That liquid which could not be decanted off was
gravity filtered through cotton. The solution was evaporated in vacuo to
minimal volume, and the crude product was extracted with methylene
chloride and evaporated in vacuo. The residue was dissolved in methylene
chloride/hexane (3:1) and chromatographed on a silica gel column with
methylene chloride/hexane (3:1). 2,7,12,17-Tetrapropylporphycene 12

was the only nonpolymeric product obtained. Recrystallization from

l2
methylene chloride/methanol (1:1) afforded fine violet needles. As was
true with the copper bronze in a previous step, freshly activating the zinc
and grinding it immediately before use improved the yield of this

cyclization step from a previous 18% to a much higher yield of 26%.

 

 

 

 

 

 

0.200
(Q/DIU. ) ”
.t. J.
320.0 100.9(NH/DIU.) 800.9

Figure 4. UV/Visible spectrum of 2.7,12,17-tetrapropylporphycene 12.

The uv/visible spectrum of TPPc 12 (Figure 4) shows a large Soret
band indicating high absorbance in the ultraviolet region. In the visible
region there are three Q-bands of lower intensity, the greatest of which is
at 633 nm, which makes it a candidate for use in PDT. Porphycene's

intensity near 635 nm in the visible region is greater than that of

porphyrin.

15N-2,7,12,17-Tetrapropylporphycene 17 was synthesized on a much

smaller scale using the same procedure as for non-labeled porphycene

13
except for the incorporation of the labeled nitrogen. Instead of using solid
sodium nitrite as the source of the pyrrole-N, an aqueous labeled sodium
nitrite solution was generated. Labeled nitric oxide, l5N180, was mixed
(4:1) with dioxygen, both in small portions, above an aqueous sodium
hydroxide solution protected from the atmosphere. After mixing of the
gases was complete the labeled sodium nitrite solution was stirred for 30
minutes, then used in the next step. Spectral data confirmed the structure.
1H NMR was identical to that of non-labeled TPPc 12; the mass spectrum
molecular ion rule was 482; and 15N NMR gave only one sharp singlet at 8
189.0 at 30° C and 188.7 at 0° C (Figure 5), which disagrees with the
literature value19 of 161 ppm. The 15N-TPPc and its Ni(II) and Cu(II)

complexes are being characterized by resonance Raman spectroscopy.

A portion of the TPPc 12 was converted to the copper(II) derivative
for use in the synthesis of bridged compounds. This was accomplished by
dissolving TPPc 12 in glacial acetic acid under argon with stirring.
Copper(II) acetate and sodium acetate were added, and the reaction mixture
was then refluxed for 19 hours. After cooling to RT the product was
extracted with methylene chloride, washed with water and evaporated in
vacuo to dryness. Recrystallization from methylene chloride/methanol

afforded a quantitative yield of violet crystals.

Each bridged compound resulted from a one—pot synthesis. N ,N'-
((N,N-Dimethylamino)methylene)—2,7,12,l7-tetrapropylporphycene 13
was synthesized from both TPPc 12 and Cu(II) TPPc in separate reactions
(Figure 6). Under an atmosphere of argon the porphycene was dissolved

in N,N-dimethylformamide with gentle warming. The solution was then

14

30° C

 

 

 

 

 

 

  

v r 17!?“va rfrrr .rnr n-rrrtu'rrurrrrq'vwnnrrrrrun u t u u I. "O’H'm
190 o m. .e the “9.2 see 0 3.0.! a... 1'1 1. 2 the 307.0 107.0 In.

Figure 5. 15N NMR of 15N-2,7,12,17-tetrapropy1porphycene at 30° C and

0° C.

15

 

 

Figure 6. Synthesis of N,N'-((N,N-dimethylamino)methylene)-
2,7,12,17-tetrapropylporphycene 13.

cooled to 20° C and phosphorous oxychloride was added dropwise with
stirring, maintaining the temperature at 20° C throughout the addition.
The reaction mixture was allowed to warm to RT, and was stirred under
argon for 20 hours, monitored frequently by uv/visible spectra and TLC to
assess progress of the reaction by the shape of the uv/visible sepctrum and
the amount of unreacted starting material present on TLC. The solution
was poured over ice and with stirring a 10% aqueous sodium hydroxide
solution was slowly added until the mixture was neutral. The crude
product was extracted with methylene chloride, washed with water and
evaporated in vacuo to near dryness. The residue was dissolved in
methylene chloride/methanol (10%). TLC showed two spots present and
the crude product was separated by preparative TLC with methylene
chloride/methanol (10%). Two major blue bands appeared and were
removed from the plate and the products isolated. However, on TLC the

product from each band separated into two spots with similar Rf values,

16

appearing to be the same compound. The crude products from the two
bands were combined, dissolved in methylene chloride and
chromatographed on a silica gel column with methylene chloride/
triethylamine (3 drops). The bridged product was isolated as a single
fraction and evaporated in vauco to dryness. Again, the TLC of this
product showed two spots which eventually converged into one spot when
left in the eluent for a longer period of time. Each blue band from the
plate and later the chromatographed product behaved in a similar manner
producing the same TLC Rf values. The conclusion drawn from this
behavior was the two bands or spots on TLC are a phenomenon caused by
the silical gel and they represent the N-protonated and nonprotonated
forms of the same compound.

Spectral data confirms the structure of N,N'-((N,N-
dimethylamino)methylene)-2,7,12,17-tetrapropylporphycene 13. In the 1H
NMR (Figure 7) the peak at 8 6.08 (1H, s, NH) indicates the proton is in a
benzylic-like position. The protons of the amino methyls and the proton on
the methylene bridge are quite shielded by the aromatic ring current and
appear at 8 -1.78 and -5.06 respectively. The uv/visible spectrum (Figure
8) is of the shape which has been characteristic of all the bridged
compounds, the three Q-bands merge into one peak around 618 nm (with
absorbance about half that of the Soret band) with a broad shoulder peak
around 583 nm, and a broadened Soret band. The structure is also
supported by the mass spectrum, which shows the M+1 peak at m/e 534.
This product, as with all of the bridged compounds, resisted attempts to
recrystallize it; upon drying, a film coated the flask but no crystals formed.
The amorphous solid was dark blue upon drying.

17

1&7

NI

pppc.__~ppcp.._p—prP_b...prbhbpbhprT.pPpppp—chbn.pppbpppbbpppp—p.+pbpp-._..

o

 

L

4

fl

 

m

 

 

.2 ocoohneainoaaboa
-5_.N_.A.N-38350885823056-2.23-2.2 as 8.508” «22 z. s 2:3...

v

 

A

74

 

3

 

44.809 ; ‘fi 4'

 

 

 

 

+e.eeo , u, , , - N
320-9 180.0(NH/DIU.) 860.8

 

 

Figure 8. UV/Visible spectrum of N,N'-((N,N-dimethylamino)methylene)-
2,7,12,17-tetrapropylporphycene 13.

The product was sent to Professor S.-M. Peng's laboratory at National
Taiwan University for crystallization and x-ray crystallography. In order
to improve crystallinity, they attempted to prepare the Cu(II) complex of
this compound by heating it with Cu(ClO4)2 in CH3CN. The product
finally crystallized to reveal an x-ray structure as shown in Figure 9. This
structure confirms the N,N'-bridged positions, but showed a
monomethylamine on the bridging methylene, N,N'-((N-methylamino)
methylene)-2,7,12,17-tetrapropylporphycene 14. A review of all of our
data confirmed that the product sent to them was indeed a dimethylamine.
An as yet unknown process caused the loss of one methyl during
crystallization. This finding caused us to attempt crystallization in the

manner used by the outside laboratory that would duplicate their findings,

19

.3 ozooEEoEangorhfimfifiNAoco—zfioa
AoEEaEEoEiVVJZi .3 2385 emanacwozfimio buxom d Enwi

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80 e «.0 meo So to e «me

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20 e e

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20
producing the monomethylamine product. N,N'-((Dimethylamino)
methylene)-2,7,l2,17-tetrapropylporphycene 13 was dissolved in
acetonitrile and a small amount of copper(II) perchlorate was added. The
mixture was heated to reflux and refluxed to dryness. Although
recrystallization attempts were unsuccessful, the mass spectrum supports

the monomethylamine structure with the molecular ion peak at m/e 519.

Several attempts were made to incorporate a methyl (instead of the
methine proton) on the methylene bridge using acetamide as the reagent.
In monitoring the progress of the reaction, no hint of a product was ever
apparent on uv/visible spectra or by TLC. The substituent on the
methylene bridge lies very nearly in the plane of the porphycene ring and
steric constraints appear to restrict this substituent to a proton only. The
molecular model of this compound shows very little available space for the
substituent.

N,N'-((N-Methylaniline)methylene)-2,7,l2,17-tetrapropyl-
porphycene 15 was synthesized (Figure 10) by dissolving TPPc 12 in 1,2-
dichloroethane under argon with gentle heating. The solution was cooled
and N-methylformanilide was added, followed by the dropwise addition of
phosphorous oxychloride. The reaction mixture was allowed to come to
RT and was stirred under argon with monitoring for 4 days, when it was
poured over ice. 10% Aqueous sodium hydroxide was added slowly with
stirring until the solution was neutral. The product was extracted with
methylene chloride, washed with water and evaporated in vacuo to near
dryness. The residue was dissolved in methylene chloride and

chromatographed on a silica gel column with methylene chloride. Polarity

21

 

 

Figure 10. Synthesis of N,N'-((N-methylaniline)methylene)-2,7,12,17-
tetrapropylporphycene 15.

of the eluent was increased by adding methanol (to 10%) to remove the
blue product, which was evaporated in vacuo to dryness. Again, attempts
to recrystallize the product were unsuccessful. The uv/visible spectrum
(Figure 11) was characteristic of the bridged products. The mass spectrum
gave M+1 as m/e 596.

 

+1.750

<223I3.>{

 

 

 

 

 

 

320.0 100.0(NH/DIU.) 800?:

Figure 11. UV/Visible spectrum of N,N'-((N-methylaniline)methylene)-
2,7 , 12,17-tetrapropylporphycene.

22
Proton NMR (Figure 12, next page) confirmed the structure. The protons
on the phenyl ring are shifted upfield due to the shielding by the ring
current and appear at 8 6.41 (para), 5.92 (meta) and 3.07 (ortho). The
amino methyl protons appear at 8 -2.11 and the methylene bridge proton
appears at 8 -5.99.

N,N'-(C-C=C-NMe2)-2,7,12,l7-tetrapropylporphycene 16 was
synthesized in a procedure similar to the previous bridged compounds
(Figure 13).

 
 
 

0
ll
H—C—C-C=C-NMez>
1>oc13

 

 

12

Figure 13. Synthesis of N,N'-(C-C=C-NMe2)-2,7,12,17-
tetrapropylporphycene 16.

To prevent polymerization of the reagent, 3-(dirnethylamino)-acrolein was
dissolved in cold 1,2-dichloroethane before adding it to the cold
porphycene solution. The reaction was again monitored by uv/visible
spectra and TLC. At 3 days the reaction mixture showed no remaining

starting material, was poured over ice and 10% aqueous sodium hydroxide

23

.3 Boga—Eon—angou

Awfi.Reasseseoszsaase-z?z.z .6 838% ”:22 E .2 28E

 

 

m

pPhpbbipbnrh»

 

 

 

 

v

rbpbpbb

 

i4

L

j

 

g

 

3

brpb—>>»>b>upb—bnptbprnth.
|

J

 

1.1..

 

24
was slowly added until the solution was neutral. The organic layer was
separated, washed with water and evaporated in vacuo to near dryness.
The. crude product was chromatographed on a silica gel column. In the
first attempt at purification of this product the polarity of the solvent was
changed with methanol (10%) which instantly decomposed the product to
starting material. In subsequent attempts acetonitrile was used to
successfully remove the product from the column. Attempts to
recrystallize this product were unsuccessful. UV/visible spectra

consistently gave evidence that a bridged product was formed (Figure 14),

 

+2.een ‘i r ‘ 1

 

+0.009

A

300.0 100.0(NH/DIU.) 800?:

 

 

il-

 

Figure 14. UV/Visible spectrum of N,N'-(C-C=C-NMe2)-2,7,l2,17-
tetrapropylporphycene 16.

however, it is a very labile product and did not withstand direct electron
impact, DCI, nor FAB mass spectra attempts. NMR results were

inconclusive due to lack of purification.

EXPERIMENTAL

Proton nuclear magnetic resonance spectra were obtained on a
Varian Gemini 300 FT N MR spectrometer. All chemical shifts were
recorded in parts per million (ppm) relative to tetramethylsilane. l5N
Nuclear magnetic resonance spectra were obtained on a VXR 500 NMR
spectrometer using a saturated aqueous sodium nitrite solution with the
peak at 228.9 ppm as the internal standard. Melting points were obtained
with an electrotherrnal melting point apparatus and are uncorrected.
UV/visible spectra were obtained on a Shimatzu UV-160
spectrophotometer. Preparative thin layer chromatography plates from
Analtech were used (silica gel GF, 1000 or 1500 um), and in column
chromatography 200-400 mesh silica gel was used. Mass spectral
determinations were made on a Fisons TRIO-1 GC-MS mass spectrometer
purchased under an NIH Shared Instrumentation Grant (SlORR06506-01).

24-Di x nl- -m --r l l

Ethyl butyrylacetate (98%) 3 (100 g, 0.62 mol) was dissolved in
glacial acetic acid (125 mL), and a saturated aqueous solution of sodium
nitrite (43.5 g, 0.63 mol) was added dropwise with stirring. The reaction
mixture was kept under 20° C with an ice water bath. After addition was
complete the reaction mixture was stirred for an additional 2 hours,

forming oxime 4.

25

26

Ethyl acetoacetate 5 (79.4 g, 0.61 mol) was dissolved in glacial
acetic acid (250 mL). With stirring, zinc powder (30 g) was added, then
the above oxime solution 4 was dropped in slowly. Additional zinc
powder (150 g) was added in small portions until the oxime addition was
finished. The reaction temperature was maintained below 75° C. After the
addition was complete, the reaction mixture was heated to 80° C and
stirred for 1 hour. The reaction mixture was cooled to 60° C and poured
into ice water (2 L). The crude product, pyrrole 6, was precipitated as a
yellow solid which was collected by filtration, washed with water and dried

in air. Recrystallization from methanol gave yellowish white plates (101 g,
62%), m.p.: 100-102° C. 1H NMR (CDC13): 8 9.70 (1H, 3, br, NH), 4.28
(4H, m COzCflgCHg), 3.00 (2H, dd, CH2CH2CH3), 2.49 (3H, s, CH3), 1.53
(2H, m, CH2CH2CH3), 1.34, 1.32 (3H each, t, C02CH2C_I-_I_3), 0.92 (3H, t,
CH2CH2CH3).

 

2,4-Diethoxycarbonyl-5-methyl-3-propyl pyrrole 6 (150 g,
0.562 mol) was dissolved in a mixture of formic acid (405 mL), glacial
acetic acid (405 mL) and acetic anhydride (90 mL) by warming on a steam
bath. The hot solution was stirred, cooled in an ice bath and put under
nitrogen. Bromine (97.5 g, 31.5 mL, 0.6 mol) was added dropwise over a
lS-minute period with stirring. Sulfuryl chloride (273.3 g, 165 mL, 2.0
mol) was added dropwise with vigorous stirring over a 3 hour period,
during which time the reaction temperature was kept below 10° C.

The reaction mixture was kept at 05° C overnight, without
stirring, fitting the flask with a drying tube. Water was slowly added to

the solution with swirling until the bubbling (with addition of water)

27

stopped. The solution was poured into water (2 L) causing the crude
product to precipitate as a peach solid suspended on the top as a thick layer.
After standing for 30 minutes, the solid was filtered, well washed with
water and suction dried. The crude product was dissolved in a minimal
volume of ethanol (550-600 mL) while heating on a steam bath, and treated
with sodium bicarbonate (87.5 g) in small portions with swirling. The
reaction mixture was then diluted with water (1250 mL). After standing
for 30 minutes the insoluble byproduct was removed by gravity filtration
through cotton. The filtrate was cautiously acidified with concentrated
hydrochloric acid (40 mL) with stirring. The precipitated product,
pyrrole 57 was filtered, washed with water to neutral, and dried in air as a
very light yellow-green powder (129.98 g, 77.9%), m.p.: 136-137° C. 1H
NMR (CDC13): 8 14.82 (1H, s, COzH), 10.34 (1H, 3, br, NH), 4.49, 4.39
(2H each, q, COzCH2CH3), 3.08 (2H, dd, CH2CH2CH3), 1.57 (2H, m,
CH2CI_-l_2CH3), 1.48, 1.41 (3H each, t, C02CH2CH3), 0.96 (3H, t,
CH2CH2CH3).

24-Di x nl--i --r l rrl
2,4-Diethoyxcarbonyl-3-propyl-5-carboxylic acid pyrrole 7 (60
g, 0.2 mol) was dissolved in 1,2-dichloroethane (300 mL). Sodium
bicarbonate (67.2 g, 0.8 mol) and water (500 mL) were added, and the
reaction mixture was heated on the steam bath. Upon warming, the
starting material dissolved with effervesence. To this mixture a solution of
iodine (55.8 g, 0.22 mol) and potassium iodide (99.6 g, 0.6 mol) in water
(300 mL) was added dropwise over a 10-minute period, with stirring. The
solution was refluxed for 1 hour, and the excess iodine was destroyed with

a solution of sodium bisulfite (10 g) in water (20 mL). The reaction

28

mixture was cooled in an ice bath and methylene chloride (400 mL) was
added. The organic phase was separated, washed with water, heated on the
steam bath and evaporated to minimal volume (200 mL). Ethanol (250
mL) was added, and the reaction mixture was heated to boiling and
removed from the heat. The product was recrystallized by adding water
(20 mL). White needle and powder crystals formed which were collected
by filtration, washed with cold ethanol/water (30%) and air dried. More
pyrrole 8 was recovered from the mother liquor (66.08 g, 83.6%), m.p.:
153-155° C. 1H NMR (CDC13): 8 9.98 (1H, s, br, NH), 4.38 (4H, m,
COzCIizCHg), 3.06 (2H, dd, CH2CH2CH3), 1.57 (2H, m, CH2CH2CH3),
1.40, 1.39 (3H each, t, COZCH2CHJ), 0.95 (3H, t, CH2CH2CH3).

 

The procedure previously used by Grigg20 was followed. 2,4-
Diethoxycarbonyl-S-iodo-3-propy1 pyrrole 8 (80 g, 0.211 mol) was
dissolved in N,N-dimethylformamide (400 mL), and freshly ground
copper bronze (80 g) was added. The mixture was stirred at RT for 20
hours. The copper was then filtered and washed with hot chloroform (200
mL X2). The filtrate and washings were combined and washed with 1N
hydrochloric acid (400 mL X2) and water (400 mL X2). The solvent was
evaporated in vacuo, and the cmde product was recrystallized from
methylene chloride/methanol (1:1) to give long white needles which were
filtered, rinsed with methanol and allowed to air dry (34.47 g, 64.8%),
m.p.: 156-158° C. 1H NMR (CDC13): 8 14.18 (2H, 3, br NH), 4.40 (8H,
m, C02CH2CH3), 3.08 (4H, dd, C_112CH2CH3), 1.58 (4H, m, CH2CH2CH3),
1.43 (12H, t, C02CH2CH3), 0.98 (6H, t, CH2CH2CH3).

29

4 4'- ° - '- '

3,3',5,5'-Tetraethoxycarbonyl-4,4'-dipropyl-2,2'-bipyrrole 9
(53 g, 0.105 mol) was added to ethylene glycol (1800 mL) with stirring,
under nitrogen. A solution of sodium hydroxide (45.18 g) in water (300
mL) was added. The reaction mixture was gently refluxed for 24 hours.
The heat was removed and the solution was allowed to cool to below 100°
C. The solution was poured into ice water (6 L), forming a fine bluish
gray precipitate throughout. After sitting 1 hour, the product was filtered,
washed with water to neutral and allowed to air dry to gray powder (22.11
g, 97.1%), m.p.: l39-140° C (dec). 1H NMR (DMSO'd6)I 8 10.46 (2H, s,
br, NH), 6.52, 6.07 (2H each, s, br, pyrrole-Ha), 2.44 (4H, t,
CH2CH2CH3), 1.62 (4H, sext, CH2CH2CH3), 0.96 (6H, t, CH2CH2CH3).

 

4,4'-Dipropyl-2,2'-bipyrrole 10 (36.45 g, 0.169 mol) was
dissolved in warm, dry N,N-dimethylformamide (1170 mL) under a
nitrogen atmosphere. The solution was cooled to 20° C in an ice bath.
Benzoyl chloride (128.85 g, 106.4 mL, 0.917 mol) was added dropwise
with stirring, keeping the temperature at 20° C. The cold water bath was
removed and the solution was allowed to sit for 5 minutes at RT, then it
was heated to 100° C where it was kept for 18 hours under nitrogen.

The reaction mixture was cooled to RT and poured into cold
water (1800 mL). 10% Aqueous sodium hydroxide solution (60 mL) was
added slowly with stirring until precipitate formed and the smell of amine
was apparent and persistent.

The precipitate was collected on celite, washed with water,

rinsed with methanol and dried. The crude product was extracted from the

30

celite with hot chloroform (1800 mL) and the solvent was evaporated in
vacuo. The residue was recrystallized in a minimal volume of methylene
chloride/methanol (2%). The gold powdery crystals were filtered and
allowed to air dry (28.0 g, 61.0%), m.p.: 232-234° C (dec). 1H NMR
(CDC13): 8 12.25 (2H, 3, br, NH), 9.62 (2H, s, CHO), 6.46 (2H, s,
pyrrole-H5), 2.73 (4H, t, CH2CH2CH3), 1.70 (4H, sext, CH2CHgCH3), 0.98
(6H, t, CH2CH2CH3).

2 12 1 -T r 1 h n ‘

Freshly activated zinc dust (28.99 g, 0.443 mol) was suspended
in dry THF (800 mL) under an atmosphere of nitrogen with stirring.
Titanium tetrachloride (42.2 g, 24.4 mL, 0.223 mol) was added dropwise
to the stirring reaction mixture. The solution was heated to reflux and
refluxed for 15-20 minutes.

4,4'-Dipropyl-5,5'-dicarbaldehyde-2,2'-bipyrrole 11 (6.0 g,
0.022 mol) was dissolved in dry THF (500 mL) and pyridine (29 mL) and
added fast dropwise to the gently refluxing titanium reaction mixture.
After addition the reaction mixture was refluxed another 1 hour. The heat
was removed and the reaction flask was cooled to RT in cold water. An
aqueous solution of potassium carbonate (41.7 g, 125 mL H20) was added
slowly and the reaction mixture was allowed to sit for 36 hours. Most of
the liquid was decanted off, the rest of the mixture was gravity filtered
through cotton. The filtrate was evaporated in vacuo to minimal volume,
dissolved in methylene chloride and separated. The organic layer was
evaporated in vacuo, and the resulting solid was dissolved in a minimal
volume of methylene chloride/hexane (3:1) and chromatographed on a

silica gel column with methylene chloride/hexane (3:1). Recrystallization

31
from methylene chloride/methanol (1:1) afforded fine violet needles (1.35
g, 25.6%), m.p.: 192-194° C. 1H NMR (CDC13): 8 9.70 (4H, s, bridge H),
9.28 (4H, s, pyrrole HB), 4.01 (8H, t, CH2CH2CH3), 3.25 (2H s, br, NH),
2.41 (8H, sext, CH2CH2CH3), 1.34 (12H, t, CH2CH2CH3); mass spectrum,
m/e 478.

”WWW

Labeled nitric oxide, 15N130, (2.39 g, 1629 mL, 0.072 mol) was
mixed with dioxygen (0.67 g, 470 mL, 0.021 mol), both in small portions
by a gas syringe, above an aqueous solution of sodium hydroxide (4.0 g,
0.10 mol, 20 mL H20), protected from the atmosphere. The solution was
stirred for an additional 30 minutes after mixing of the gases was
complete.

This step involving the incorporation of labeled nitrogen into the
aqueous sodium nitrite solution was the only step which was different
from the synthesis of nonlabeled 2,7,12,17-tetrapropylporphycene; all
subsequent steps were the same as above. 15N NMR (CD2C12): 8 189.0 (s)
at 30° C and 188.7 (s) at 0° C; mass spectrum, m/e 482.

- - l h
2,7,12,l7-Tetrapropylporphycene 12 (0.050 g, 0.105 mmol) was
dissolved in glacial acetic acid (37.5 mL) under argon. Copper(II) acetate
(0.0125 g, 0.626 mmol) and sodium acetate (0.008 g) were added with
stirring. The reaction mixture was heated under argon to reflux and
refluxed for 19 hours, then allowed to cool to RT. The reaction mixture
was partitioned in methylene chloride (250 mL) and water (250 mL). The

organic layer was separated, washed with water (250 mL) and evaporated

32
to dryness. Recrystallization from methylene chloride/methanol gave a
quantitative yield of violet crystals.

L - L-Du‘J 211.10 1171. ‘i‘ - _ -: turn Mn ‘1‘
1.2

2,7,12,17-Tetrapropylporphycene 12, or Cu(II)-2,7,12,17-
tetrapropylporphycene (0.50 g, 0.105 mmol) was dissolved in N,N-
dimethylformamide (75 mL) under an atmosphere of argon with gentle
warming. The solution was cooled to 20° C and phosphorous oxychloride
(8.23 g, 5 mL, 0.054 mol) was added dropwise with stirring, maintaining
the temperature at 20° C during the addition. The reaction mixture was
allowed to warm to RT, and stirring under argon was continued for 20
hours. The solution was poured over ice (50 g) and 10% aqueous sodium
hydroxide (100 mL) was added slowly with stirring. The product was
extracted with methylene chloride (500 mL) and washed with water (200
mL). The organic layer was evaporated in vacuo to near dryness. The
residue was dissolved in methylene chloride/methanol (10%) and separated
by preparative TLC. The crude product was dissolved in dichloromethane
and chromatographed on a silica gel column (2 x 18 cm) with methylene
chloride/triethylamine (3 drops). The bridged product was evaporated in
vacuo to dryness. 1H NMR (CDC13): 8 10.34, 10.07 (2H each, 3, bridge
H), 9.98, 9.67 (2H each, s, pyrrole HB), 6.08 (1H, 3, NH), 4.15, 3.98 (8H,
m, CH2CH2CH3), 2.40 (8H, m, CH2CH2CH3), 1.29 (12H, dt, CH2CH2CH3),
-1.78 (6H, s, N-Cflg), -5.06 (1H, s, CH); mass spectrum, m/e 534 (M + 1).

33
'- butt) -1 -_ 11-10 11’ -l ‘1‘---‘._t€' o I H u 1 111‘
N,N'-((N,N-Dimethylamino)methylene)-2,7,12,17-tetrapropyl-
porphycene 13 (0.040 g, 0.075 mmol) was dissolved in acetonitrile (30
mL) and a small amount of copper (H) perchlorate (10-15 mg) was added.
This mixture was brought to reflux on the steam bath and was refluxed to
dryness. Mass spectrum, m/e 519.

N'- \-U‘.! .-..1____!'11,‘.1 ‘1‘--‘.t’20 H ru- :1‘

2,7,12,17-Tetrapropylporphycene 12 (0.050 g, 0.105 mmol) was
dissolved in 1,2-dichloroethane (75 mL) under argon with gentle heating.
The reaction mixture was cooled to 5° C and N-methylformanilide (0.142
g, 0.13 mL, 1.05 mmol) was added under argon with stirring.
Phosphorous oxychloride (8.23 g, 5 mL, 0.054 mol) was added dr0pwise
over 5 minutes with stirring. The solution was allowed to come to RT and
stirring under argon was continued for 4 days. The reaction mixture was
poured over ice (50 g) and 10% aqueous sodium hydroxide (100 mL) was
added slowly with stirring. The product was extracted with methylene
chloride (500 mL) and washed with water (200 mL). The organic layer
was evaporated in vacuo to near dryness. The residue was dissolved in
methylene chloride and chromatographed on a silica gel column (1.5 x 15
cm). The product was evaporated in vacuo to dryness. 1H N MR (CD3CN):
8 10.30, 9.29 (2H each, 3, bridge H), 9.12, 8.82 (2H each, s pyrrole HB),
6.41 (1H, t, p-Ph-H), 5.92 (2H, t, m-Ph-H), 4.30, 4.07, 3.64 (2H, m, 2H,
m, 4H, m,CH_2CH2CH3), 3.07 (2H,d, o-Ph-H),2.33, 2.21 (4H each, m, m,
CH2CH2CH3), 1.45, 1.28 (6H each, t, t, CH2CH2CH3), -2.11 (3H, s, N-CH3),
-5.99 (1H, s, OH); mass spectrum, m/e 596 (M + 1).

34

NN'- - = - _-2 1 l7-T r l n

2,7,12,17-Tetrapropylporphycene 12 (0.050 g, 0.105 mmol) was
dissolved in 1,2-dichloroethane (75 mL) under argon with stirring and
gentle warming. The solution was cooled to 5° C. 3-(Dimethylamino)-
acrolein (0.104 g, 0.105 mL, 1.05 mmol) was dissolved in cold (5° C) 1,2-
dichloroethane (15 mL) and added to the reaction mixture, followed by the
dropwise addition of phosphorous oxychloride (8.23 g, 5 mL, 0.054 mol)
over a 5 minute period. The reaction mixture was allowed to warm to RT,
and stirring under argon was continued for 3 days. The reaction mixture
was poured over ice (50 g), and 10% aqueous sodium hydroxide (50 mL)
was added slowly with stirring. The organic layer was separated and
washed with water (100 mL), then evaporated in vacuo to near dryness.
The crude product was dissolved in methylene chloride/acetonitrile and
chromatographed on a silica gel column (1.5 x 14 cm) prepared with
methylene chloride. The product was evaporated in vacuo to dryness.

Attempts to recrystallize the product were unsuccessful.

Attempts to prepare:
N-Methyl-2.7,12.17-tetrapropylporphycene
2,7,12,17-Tetrapropylporphycene 12 (0.050 g, 0.105 mmol) was
dissolved in a soultion of m-xylene (85 mL), glacial acetic acid (5 mL) and
iodomethane (10 mL) under argon. The solution was refluxed for 27
hours. No trace of N-methylporphycene was indicated by uv/visible
spectrum nor TLC.
Trichloroacetic acid (5.15 g) was dissolved in a solution of m-
xylene (15 mL) and iodomethane (10 mL) and was added to the reaction

mixture. Refluxing was continued for another 3 days. The uv/visible

35
spectrum is indicative of an N -substituted TPPc as it is of the same shape as
the bridged porphycenes, and unlike the shape of TPPc, however, N-
methylporphycene has not been isolated.

FUTURE WORK

Because of the great stability of the N,N'-bridged porphycenes, they
may provide interesting ways to build suprastructures on the macrocycle.

Work in the series of N,N'-bridged porphycenes will continue.
Planned first is the synthesis of N,N'-((morpholine)methylene)-2,7,12,17-
tetrapropylporphycene 17 (Figure 15), following a procedure similar to
that used previously. A 5-fold excess of 4-formylmorpholine will be used
and the reaction mixture will be heated to 50° C and kept there as the
progress of the reaction is monitored by uv/visible spectra and TLC.

Workup will be accomplished in the same manner as before.

 

 

17

Figure 15. Synthesis of N,N'-((morpholine)methy1ene)-2,7,12,17-
tetrapropylporphycene 17 .

36

37
The synthesis of other N-substituted porphycenes will be attempted.

The first reaction attempted will be the addition of carbenes generated by
CHC13 and NaOH in various alcohols to produce alkoxy-substituted
methylene-bridged porphycenes (Figure 16).

ROH

 

#
CHC13

NaOH, H20
TEBA

 

Figure 16. Synthesis of N-alkoxy-2,7,l2,17-tetrapropylporphycene 18.

Also planned is to connect two 2,7,12,l7-tetrapropylporphycenes
with methylene bridges using piperazine as the connector (Figure 17). The
reagent that will be used to accomplish this is 1,4-piperazine-
dicarboxaldehyde. It is hoped that this compound may be of value as a
PDT agent, much like porphyrin dimers.

38

 

 

Figure 17. Synthesis of 2,7,12,17-tetrapropylporphycene dimer with
piperazine connector.

LIST OF REFERENCES

REFERENCES

. Jesionek, A.; Tappeiner, V.H. Muench Med. Wochenshr. 1903, 47,
2042.

. Dougherty, T.J.; Smith, K.M. J. Chem. Soc. Perkin TransJ 1992,
1337, and references therein.

. Pass, H.I.; Delaney, T.F. In Cancer 4th Ed.; DeVita, V.T., Hellman, S.,
Rosenberg, S.A., Eds.; J .B. Lippincott Co.: Philadelphia, 1993, p
2689.

. Lin, C-W. In Photodynamic Therapy of Neoplastic Disease; Kessel D.,
Ed.; CRC Press: Boston, 1990, pp 79-101.

. Pass, H.I.; Chest Surg. Clin. North Am. 1991, I , 135.

. a) Chemical Abstracts, 1993, 119, 1044 (PCT Int. Appl W0 93
00,087); b) Chemical Abstracts, 1993, 118, 815 (PCT Int. Appl W0
92 12,636); c) Chemical Abstracts, 1993, 118, 6794 (US 5,132,101);
(1) Chemical Abstracts, 1990, 113, 70 (US 4,913,907).

. Vogel, E.; Kocher, M.; Schmickler, H.; Lex, J. Angew. Chem. Int. Ed.
Engl. 1986, 25, 257.

. Aramendia, P.A.; Redmond, R.W.; Nonell, S.; Schuster, W.;
Braslavsky, S.E.; Schaffner, K.; Vogel, E. Photochem. Photobiol.
1986, 44, 555.

. a) Johnson, A.W.; Ward, D.; Batten, P.; Hamilton, A.L.; Shelton, G.;
Elson, C.M. J. Chem. Soc., Perkin Trans. I 1975, 2076; b) Johnson,
A. W.; Ward, D. J. Chem. Soc., Perkin Trans. I 1977, 720.

10. Callot, H.I.; Fischer, J .; Weiss, R. J. Am. Chem. Soc., 1982 104,

1272.

39

11.

12.

13.

14.

15.

16.
17.

l8.

19.

20.

40

a) Ortiz de Montellano, P.R.; Mathews, J .M. Biochem. J. 1981, 195,
761. b) Ortiz de Montellano, P.R.; Mathews, J .M.; Lanory, K.G.
Tetrahedron 1984, 40, 511.

Lavellee, D.K.; The Chemistry and Biochemistry of N-Substituted
Porphyrins, VCH Publishers: New York, 1987; p 181.

Kunze, K.L.; Ortiz de Montellano, P.R. J. Am. Chem. Soc. 1981,
103, 4225.

Lavelle, D.K.; Gebala, A.E. Inorg. Chem. 1974, 19, 2004.
Cavaleiro, J .A.S.; Condesso, M.F.P.N.; Jackson, A.H.; Neves,
M.G.P.M.S.; Rao, K.R.N.; Sadashiva, B.K. Tetrahedron Lett. 1984,
25 , 6047.

Latos-Grazynski, L. Inorg. Chem. 1985, 24, 1681.

Callot, H.J. Tetrahedron Lett. 1979, 33, 3093.

Vogel, E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J .; Ermer, 0.
Angew. Chem. Int. Ed. Engl. 1987, 26, 928.

Wehrle, B.; Limbach, H.-H.; Kocher, M.; Ermer, 0.; Vogel, E.
Angew. Chem. Int. Ed. Engl. 1987, 26, 934.

Grigg, R. J. Chem. Soc., Perkin Trans. I 1972, 2111.

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