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SYNTHESIS OF PORPHYRINS AND DIPORPHYRINS
AND THEIR BIOMIMETIC APPLICATIONS

presented by
Ching-Bore Wang

has been accepted towards fulfillment
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Ph . D. degreein Chemistry

 

 

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Major professor

 

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SYNTHESIS OF PORPHYRINS AND DIPORPHYRINS
AND THEIR BIOMIMETIC APPLICATIONS

By
Ching-Bore Wang

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1981

ABSTRACT

SYNTHESIS OF PORPHYRINS AND DIPORPHYRINS
AND THEIR BIOMIMETIC APPLICATIONS

By
Ching-Bore Wang

A series of difunctional Czh symmetry porphyrins were
synthesized by condensation of pyrrole aldehydes and pyrrole
acids. The porphyrins can be obtained in large scale by this
method. Some porphyrins with one, two, three and four
carboxyester side chains were prepared by condensation of
5,5'-dibromopyrromethene and 5,5'-dimethylpyrromethene. Most
of the porphyrins can be obtained from the simple 5-methyl-2-
carbonylpyrrole ester.

From the C-13 nmr chemical shift of the B-carbons, the
structure of porphyrins can be determined. The CB-Me's
chemical shift were affected by their neighbor substituents.

Several cofacial and slipped diporphyrins were syn-
thesized by coupling of 1,5-difunctional porphyrins with 1,5-
and 1,4-difunctional porphyrins in amide bonds. The applica-
tion of dimers as a photosynthesis reaction center model and
sterically binded myoglobin binding site model were discussed.

A series of porphyrin- and chlorin-quinone compounds
were prepared. Their photopotentials were compared with

chloroplast on bilayer lipid membrane.

ACKNOWLEDGMENTS

I wish to express my sincere appreciation to Professor
C. K. Chang for his encouragement, guidance and confidence
throughout the course of this study.

I am very grateful to Dr. J. Fajer for the financial
support for me to stay at Brookhaven National Laboratory.
Many thanks also go to the colleagues at BNL for the help,
discussion and friendship.

I would also like to thank Drs. M. S. Kuo and F. Ebina,
and R. Young and B. Ward for all the help, discussion and
friendship.

Appreciation is extended to the National Science
Foundation for financial support in the form of research
assistantships.

My thanks go to my parents and my wife, Shu-Ching, for

their support and constant encouragement during these years.

ii

TABLE OF CONTENTS

CHAPTER 1 INTRODUCTION.
PHOTOSYNTHESIS .
PYRROLE AND PORPHYRIN SYNTHESIS.

CHAPTER 2 SYNTHESIS OF PYRROLES AND
PORPHYRINS . .

INTRODUCTION
RESULTS AND DISCUSSION
Pyrrole synthesis .
Czh (type II) porphyrins synthesis-

Synthesis of porphyrins with one, two (C v)
three and four carboxylic acid side chai

C-13 nuclear magnetic resonance of porphyrins -
EXPERIMENTAL -

Reagents and solvents ~

Physical and spectroscopic methods-

General procedure for the synthesis of 3- alkyl-
2, 4- -pentanediones . . . .

3-Ethyl-2,4-hexanedione-BF2 complex -
3-Ethyl-2,4-hexanedione 3d-
3-Pentyl-2,4-pentanedione BF2 complex -
3-Pentyl-2,4-pentanedione 3a-

Ethyl-3-acetyl-4-ox0pentanoate 3c -

The general procedure of the synthesis of pyrroleso

Page

12
12
14
14
18

20
26
32
32
32

33
33
33
34
34
34
35

Benzyl 3,5-dimethylpyrrole-Z-carboxylate 4e .
Benzyl 4-pentyl~3,5-dimethylpyrrole-Z-carboxylate 4a.

Benzyl 4- methylcarboxyethyl- 3, 5- -dimethylpyrrole- 2-
carboxylate 4b.. .

Benzyl 4- -ethylcarboxymethyl- 3, 5- dimethylpyrrole-O 2-
carboxylate 4c. . . .

Benzyl 3,4-diethyl-5-methyl-2-carboxylate 4d.

Benzyl 4- (1- -oxo- -hexane)- 3, 5- -dimethylpyrrole- -2-
carboxylate 5 . .

Benzyl 4-hexyl-3,5-dimethylpyrrole-Z-carboxylate 6.

Benzyl 4- (2- hydroxyethyl)- 3,5-dimethylpyrrole-2-
carboxylate 7 . . . . . . . . . . . . . .

Benzyl 4- (2- chloroethyl)- 3, 5- dimethylpyrrole- 2-
carboxylate 8 . . .

Benzyl 5- -formyl- 4- hexyl- -L -methylpyrrole- -2-
carboxylate 9a.. . .

Benzyl 5- formyl- 4-pentyl-3— —methylpyrrole- -2-
carboxylate 9b. . . .

Benzyl 5- -formyl- -4- -methoxycarbonylethyl- 3- methyl-
pyrrole- 2- -carboxylate 9c. . . . . .

Catalytic hydrogenolysis of benzyl ester pyrroles
or dipyrromethanes. . . . . . . . . . . . . .

General synthesis procedure of the Czh porphyrins

Porphyrin 12a .
Porphyrin 12b .
Porphyrin 12c
Porphyrin 12d .
Porphyrin 12e
Porphyrin 13.
Porphyrin 14.
Porphyrin 15.

3,3' -(2- Hydroxycarbonylmethyl)- 2, 2', 4 ,4'-tetramethyl-
5,5' -dipyrromethenium bromide 16a . . . .

iv

40
4o
41
41
42
42
42
42
43
43

.43

3,3'-(2-Methoxycarbonyl)-2,2,4,4'-tetramethyl-5,5'-
dipyrromethenium bromide 16bO .

3,3'-(2-Chloroethyl)-2,2',4,4'-tetramethyl-5,5'-
dipyrromethenium bromide 16cO O .

5- Acetoxymethyl-O -2- ethoxycarbonyl— 3, 4- diethylpyrrole
17a . . . . . . . . . . . . . . . . . .

Benzyl S-acetoxymethyl-4-(2-chloroethyl)-3-methyl-
pyrrole-Z-carboxylate 17c . O . . O O . . . . .

Benzyl 5- acetoxymethyl- -4- hexyl- 3- methylpyrrole- 2-
carboxylate 17d. . . . . . . . . . . . .

5,5'-diethoxycarbonyl-3,3',4,4'-tetraethyl-2,2'-
dipyrromethane 18a . . . . . . . .

2,2'-Dibenzyl-3,3',4,4'—tetraethyl-2,2,-dipyrro-
methane dicarboxylate 18a', . . . O . . O

2,2'-Dibenzyl-3,3'-di(2-chloroethyl)-4,4'-dimethyl-
5,5'-dipyrromethane dicarboxylate 18cO . . . O

2,2'-Dibenzyl-4,4'-dihexyl-3,3'-dimethyl-5,5'-
dipyrromethane dicarboxylate 18d . . .

2, 2' -Dibromo- 3, 3' 4, 4' -tetraethy.l- -5 ,5'-dipyrro-
methenium bromide 19a. . . . . , . . . . .

5,5'-Dibromo-3,3'-di(2-methoxycarbonylethyl)-4,4'-
dimethyl-2,2'-dipyrromethenium bromide 19b . O O

2,2'-Dibromo-4,4'-(2-chloroethyl)—3,3'-dimethyl-
5,5'-dipyrromethenium bromide 19c, . O O O .

2,2'-Dibromo-4,4'-dihexyl-3,3'-dimethyl-5,5'-
dipyrromethenium bromide 19d . O O O O O O O

4'-(2-Hydroxycarbonylethyl)-3,4-diethyl-3',5,5'-
trimethyl-2,2'-dipyrromethenium bromide 24

Porphyrin synthesis from dipyrromethenium bromideO

Methyl- 1,2, 3,4, 5,8-—hexaethyl-6-methyl-7-propionate
porphyrin 26a. . . . . . . . . . . .

Methyl- 1, L 3, 4- -tetraethyl- 6, 7- dimethyl- -5, 8- di-
propionate porphyrin 26b O . O O O O O O O

Methyl- -1, L 3, 4- -tetraethyl- 6, 7- dimethyl- 5, 8— diacetate
porphryin 26c. . . . . . . . . . . .

43

.;44

44

45

45

46

46

47

47

47

48

48

48

48
49

SO

50

50

Methy1- -1, 4, 6, 7- tetramethy1- 2, 3- dihexyL 5, 8-
dipropionate porphyrin 26d. . . . . . . .

MethyL 1, 4, 6, 7- tetramethyL L 3- OdihexyL L 8- diacetate
porphyrin 26e . . . . . . . . . .

Methy1- -2, L 8- trimethy1- 3, 4- .diethy1- 1 6, 7- -tripropionate

porphyrin 26f

1,4-Bis(2-ch1oroethy1)-2,3,5,8-tetramethy1-6,7-
bis(2-methoxycarbony1ethy1) porphyrin 26g . . .

2,3-Bis(2-ch10roethy1)-1,4,6,7-tetramethy1-5,8-
bis(2-methoxycarbony1ethy1) porphyrin 26h . . .

MethyL 1, 4, L 8- -tetrapropionate- L 3, 6, 7- tetramethy1
porphyrin 26k . . . . . .

The dehydroch1orination of 2- ch1oroethy1. porphyrins
to viny1 porphyrins . . . .

1, 4- -Diviny1- 2, 3, 5, 8- -tetramethyL. 6, 7- bis(2- -methoxy-
carbonyl) porphyrin 26i . . .

L 3- Diviny1- 1, 4, 6, 7- -tetramethyL L 8- bi.s(2- methoxy-
carbony1) porphyrin 263 . . . . .

CHAPTER 3 SYNTHESIS OF COFACIAL AND
SLIPPED DIPORPHYRINS.

INTRODUCTION .
RESULTS AND DISCUSSION .

Synthesis of diporphyrins .

Nuc1ear magnetic resonance spectroscopy .

E1ectronic spectroscopy .

E1ectron spin resonance spectroscopy,

Cyc1ic Vo1tammetry

Oxygen interaction with dicoba1t porphyrinsO

Steric effect in oxygen and carbon monoxide bindingO

Picosecond measurement of the e1ectron transfer in
s1ipped Mg-HzDimer-SDS

EXPERIMENTAL.

Preparation of porphyrin amines.

vi

50
51 '
51
52
52
52
53
53
54

62

62
63
63
69
72
72
76
76
81

85
87
88

Reduction of diester porphyrin to dioi 28 . . . . . . . 88
Mesyiate porphyrins 29 . . . . . . . . . . . . . . . . 88
N-butyl amine porphyrins 30 . . . . . . . . . . . . . . 89
Preparation of primary amine porphyrins . . . . . . . . 89
Diacid porphryin 31d . . . . . . . . . . . . . . . . . 89
Diacid chioride porphyrin 32d . . . . . . . . . . . . . 89
Diacid azide porphyrin 33a. . . . . . . . . . . . . . . 9O
Dipropionyi azide porphyrin 33b . . . . . . . . . . . . 90
Dimethyiisocyanate porphyrin 34a. . . . . . . . . . . . 90
Diethylisocyanate porphyrin 34b . . . . . . . . . . . . 91
Dimethylamine porphyrin 35a . . . . . . . . . . . . . . 91
Diethylamine porphyrin 35b. . . . . . . . . . . . . . . 91

General procedure for the diamide-iinked
diporphyrin preparation . . . . . . . . . . . . . . . . 92

General method for copper insertion into
porphyrins and diporphyrins . . . . . . . . . . . . . . 93

General method for the preparation of Mg- Mg and

Mg- H2 diporphyrins - - - . . . . . 93
Cu-Fe dimer 4 . ... . . . . . . . . . . . . . . . . . . 94
Cu-Fe dimer 4 and dimer 5 . . . . . . . . . . . . . . . 95

CHAPTER 4 SYNTHESIS OF PORPHYRIN- AND
CHLORIN-QUINONE DONOR-ACCEPTOR PAIR. . 96

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . 96
RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . 97
EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . . 101

2,5-Diacety1 benzoic acid 40- . . . . . . . . . . . . . 102
2,5-diacety1 benzoylchloride 41 . . . . . . . . . . . . 102
2,5-dimethoxy phenyiacetyichioride 42 - - . - . - . . . 102
Diacetyi benzene porphyrin 43 - . . . . . . . . . . . . 102

vii

Dimethoxy benzene porphyrin 46.
Diacetyl benzene chlorin 49 .
Hydroquinone porphyrin 44 .
Hydroquinone porphyrin 47 .

Hydroquinone chlorin'50,o

General procedure for the preparation of quinone

porphyrins

Quinone porphyrin 45-
Quinone porphyrin 48.
Quinone chlorin 51.

REFERENCES .

viii

103
103
103
104
104

104
105
105
105
106

 

LIST OF TABLES

Czh Porphyrins .

Porphyrins with One, Two, Three and
Four Carboxyester side chains.

C-13 NMR data of some Porphyrins .
PMR and VIS spectra data of Dimers .

Redox Potential of Cobait Porphyrins
from C. V. . .

Kinetic and Equilibrium Constants for
the Binding of C0 and 02 .

ix

Page

19

24
27
71

76

84

Figure

1-1

1-2

3-7

3-8

LIST OF FIGURES

Electron Transfer Pathway of Bacterial
Photosynthesis . . . . . . . . . .

Electron Transfer Pathway of Plant
Photosynthesis . . . . . . . .

P700 Model Proposed by (a) Katz (b) Fong .
Isomers of Ur0porphyrin.

PMR Spectrum of Porphyrin 12b.

PMR Spectrum of Porphyrin 12c.

PMR Spectrum of Porphyrin 13 .

PMR Spectrum of Porphyrin 26d.

CMR Spectrum of Porphyrin 12a.

CMR Spectrum of Porphyrin 12b.

CMR Spectrum of Porphyrin 13

Cofacial and Slipped Diporphyrin

Syn and Anti Configuration of Diporphyrins
PMR Spectrum of Diporphyrin FD4.

Vis Spectra of Mg- HzFDS, Mg-H2FD4 and
0EP/MgOEP. . . . . . . . . .

ESR Spectrum of Cu-Cu F04.

ESR Spectra of u-Superoxo Co- Co Diporphyrins
A. Diporphyrin- -5 B. Diporphyrin- -4

C. Slipped Diporphyrin- 4 .

Carbon Monoxide Binding to the Stericall y
Crowded Fe- Cu Diporphyrin- 4 . . .

Excited State Spectra of Slipped Dimer 5
x

Page

11
55
56
57
58
59
60
61
65
65
7O

73

75

79

82
86

CHAPTER 1
INTRODUCTION

A great deal of effort has been expended over the past
few years in elucidating the nature of active sites in
metalloenzymes using well-defined model compounds. 0f the
many areas in which biomodeling has been undertaken, metallo-
porphyrin chemistry has been and continues to be, one of the
most fruitful. A large number of studies have centered
around simple porphyrin and metalloporphyrin system, such as
complexes of protoporphyrin IX and synthetic octaethyl-
porphyrin (OEP) and tetraphenylporphyrin (TPP) [1]. While
studies of these readily available molecules have provided
important information concerning the basic chemical and
structural properties of metalloporphyrins, these simple
models do have serious limitations in mimicking complex bio-
molecules. For example, it would be extremely difficult, if
not impossible, for the monomeric metal chelate to function
as a multinuclear metal catalysts. Clearly there is a need
for more elaborate, tailor-made model system designed to
model specific features of biological system.

The objectives of this research are:

(1) to synthesize a wide variety of dimeric cofacial

porphyrins with predetermined geometry such that

they can serve as biomimetic models for the

2
reaction centers in photosynthetic units.

(2) to synthesize a series of quinone-porphyrin and
chlorin complexes to serve as models for studying
electron transport phenomenon in photosynthesis.

(3) to develop synthetic methods for large-scale pre-
parations of pyrrol and porphyrin precursors re-
quired for the above studies.

During the course of this study, we have also used

mixed metal Cu-Fe cofacial diporphyrins as an example to
show how oxygen and carbon monoxide binding to a heme can be

modulated by local nonbonding steric effects.

(I) Photosynthesis

 

All photosynthetic organisms except bacteria use water
as electron or hydrogen donor to reduce carbon dioxide or
other electron acceptor; as a consequence they evolve
molecular oxygen. Photosynthesis developed by plants and

algae, can be simply represented as

hv
nHZO + nCO2 —) (CH20)n + n02

It should be appreciated that in addition to carbon,
hydrogen, and oxygen, the plants also incorporate nitrogen
and sulfur into organic material via light-dependent
reactions.

There are, basically, two types of photosynthesis: (a)
the water splitting variety seen in all plants and algae,
and (b) the photosynthetic bacterial type which cannot use

water as an electron donor but instead uses compounds such

3
as sulfide, organic acids, etc. In both types of photo-
synthesis, the important processes are the same: 1. light
absorption by chlorophyll-containing membrane; 2. a charge
separation across the membrane; and 3. donation and accept-
ance of electron on either side of the membrane.

(a) Bacterial Photosynthesis [2]:

 

A typical reaction center isolated from the membrane of
red and green photosynthetic bacteria has molecular weight
about 70,000 and contains four molecules of bacterio-
chlorophyll, two molecules of bacteriopheophytin, one atom
of iron, two quinone molecules, and three hydrophobic
proteins of molecular weight 20,000-30,000. Within these
reaction centers, the primary photochemistry occurs. In
addition, there are the light-harvesting or antenna bacterio-
chlorophylls (about 40 per reaction center) and their
associated proteins which are involved in the capture of
light energy and the funnelling of it to a specific reaction
center.‘

A scheme for electron transport is shown in Fig. 1-1,
which emphasizes the redox potentials. Light channeled by
the light-harvesting bacteriochlorophylls to the reaction
center is captured by a bacteriochlorophyll dimer (P870) and
within 10 ps a radical pair is formed between P870 and
bacteriopheophytin[(P870)+(BPheoT]. Within another 200 ps,
an electron is passed to the primary quinone (09 which is
associated with a nonheme iron atom; the quinone forms a

semiquinone.but then transfers the electron to the secondary

4
quinone (02). The electron then reduces a pool of ubi-

quinones (UQ) which Span the membrane and shuttle protons

EO'M
NAD’
-O.4 - BPhoo
' I
up”; \. Juo‘
\
1
’1
-O.2 - 01 (F0) ATP,-”’/
. \ fr
92 /
proton \UQ Pool
0.0 - 1mm
“'0“ CY‘ b\
when 6“ c
to m Vs 'P
V. .
ApPoP. ATP “mm"
+0 2 )-
Fo-S
W‘s/55

 

 

+06

Fig. 1-1. Electron transfer pathway of Bacterial
Photosynthesis.

back and forth across the membrane. These protons are used
for ATP formation via a chemiosmotic mechanism. The electron
completes the cycle by returning to the P870 via an Fe-S
protein (Reiske-type) and a high potential cytochrome c.

This last step probably occurs within 270 ns of the initial
light reactions, while the other reactions are occurring
simultaneously. The overall result from this cyclic process

is ATP formation, but Under certain conditions an external

5
electron donor such as succinate or sulfide can donate
electrons and, using the ATP formed in the cyclic reaction,
reduce NAD to NADH which is required for subsequent carbon
fixation.

(b) Plant Photosynthesis (£1:

The unique ability of plant (and algae) chlorophyll-
containing membranes to split water was postulated by Hill
and Bendall [3] as the so-called "2 Scheme," Fig. 1-2.
Nature has evolved a marvellous system whereby four quanta
are collected as positive charges (2+) from four successive
photoacts; these "holes" are then used to remove electrons
from H20 to produce oxygen (and protons). The light-

generated Z+ probably represents a Mn-containing complex

 

 

 

e, ' (v;
-0.0
r ..‘A
A) 1‘
’06~ (54;
I?"
-04 l- -"’o‘ ''''''' a,
-02 )- Cflb.‘---- “lupg/IK‘IIDF”
\
l) 0, r
00 )- o‘s‘Po’
A098" pool system I
ATP Info-S
0.2 - new, *\
are CV”
11 \
”“1”“ "mo.
00 0
381.388.?
0.6 )- 1.an
CW 1
H10
0.8 . 9
Egoomo.
a 9%
1.0 1E 01.92", 0093:???
Law Ham-nag
CW". 0 Mb

Fig. 1-2. Electron transfer pathway of Plant Photo-
synthesis.

6
(enzyme?) which can transfer an electron to P680+ in less
than 1 us - possibly within 30 ns in chloroplasts. (The
oxidized P680+ is generated in the initial photoact when
each photon causes one electron to be extracted from the
P680 dimer and donated within 1 ns to the primary electron
acceptor-anion of pheophytin or quinone 01.)

The primary electron acceptors of photosystem II
(pheophytin, Q1 and 02) pass electrons singly within a milli-
second to a plastoquinone pool which then shuttles protons
and electrons across the membrane. In this way, a proton
gradient is built up (often as high as 2.5-3.5 pH units from
the outside to the inside of the membrane) which is sub-
sequently used for ATP synthesis via a chemiosmotic mechanism,
as in photosynthetic bacteria. The overall stoichiometry is
thought by some to approach one ATP molecule formed for each
photosystem.

The reduced plastoquinone at the inside of the membrane
passes its electron to the oxidized P700+ chlorophyll dimer
(reaction-center trap of primary photoact results in a
charge separation across the membrane, with one electron
moved per photon. The primary electron acceptors of photo-
system I have been well explored using a variety of physico-
chemical techniques. It is believed that a redox potential
of -0.73 V, or even more negative, is generated and that A1
may be a chlorophyll anion and A2 an Fe-organic complex with
the organic part being possibly a chlorophyll a. This

primary reaction occurs in about 20 ns and then the

7
electrons are passed within 100 ns to two membrane-bound Fe-
S proteins with redox potentials of -0.59 and -0.55 V, and
thence to ferrodoxin, to flavoprotein, and finally to NADP+
to form NADPH, which is used along with the ATP for C02
reduction.

The orientation of specific pigments within the mem-
brane and the reaction centers is an active field of
research at present. The structure of the reaction center
chlorophyll is somewhat related to the hydrated chlorophyll
aggregates. Currently, it is believed that the Photosystem
I reaction center consists of a special pair of chlorophylls

bridged by two water ligands. Several models have been

proposed for P700, Fig. 1-3 [4, 5].

 

Fig. 1-3. P700 model proposed by (a) Katz (b) Fong

8
Our study of dimeric porphyrins would shine light on
the basic photochemistry in the charge separation process
and would further allow us to assess the influence of
spatial configuration and redox potential differences in

driving and controlling charge transfer kinetics.

(II) Pyrrole and Porphyrin Synthesis

 

The synthetic aspect of porphyrin chemistry has been
treated extensively in Hans Fischer's classic work "Die
Chemie des Pyrrols" (1934-40) [6]. Newer methods for syn-
thesis of porphyrins and related compounds have been sur-
veyed in excellent reviews in Dolphin's "The Porphyrins" [7].

(a) Porphyrin from pyrroles

 

The first synthesis of a porphyrin directly from the
self-condensation of a pyrrole was the formation of etio-
porphyrin from 3-methyl-4-ethyl pyrrole (opsopyrrole) [8].
In spite of the high yield and the ease of preparation this
route cannot be applied when the pyrrole has 2 different
substituents at 3 and 4 position, isomeric porphyrins will
be obtained. However, this is the method of choice in
preparing octaethylporphyrin (OEP).

(b) Porphyrins from dipyrromethenes

 

A widely used porphyrin synthesis is the condensation
of dipyrromethene in a melt of succinic or tartaric acid
which was developed by Fischer [9] in 1920. In general the
yield of porphyrins obtained by this method are low. This
method involved the condensation of hydrobromides of two

5-bromo-5'-methyldipyrromethene or the condensation of the

9

hydrobromides of a 5,5'-dimethyldipyrromethene with a 5,5'-
dibromodipyrromethene. The drastic reaction conditions,
(e.g. high temperature in acid melt) do not permit the
survival of labile substituents. Nevertheless, this route
represents the most straightforward method to prepare
porphyrins with Czh or C2v symmetry required in our dimer
synthesis.

These methods have been improved by Corwin and Sydow by
using milder conditions. Etioporphyrin copper complex was

synthesized by treatment of the dipyrromethene with boiling

BuNH
CUCl

2 ; Cu-Etioporphyrin

 

t-butylamine in the presence of cuprous chloride [10].

Smith [11] recently reported that 5-methyl-5'-bromo-
dipyrromethenium bromide gave high (40-60%) of type I
porphyrins when refluxed in anhydrous formic acid. In our
study, we have further simplified the procedures and made it

adaptable to large-scale manipulations.

Nomenclature of Porphyrins

 

Two systems [12] for numeration of the porphyrin ring
are currently in use. The IUPAC system is shown in structure
B, which was designed to achieve consistency between
porphyrins and corrins. The major disadvantage of the IPUAC

recommended system is that it may divorce contemporary

10
research from the monumental body of early work which used
the Fischer system, A. In the classical system of nomen-
clature the peripheral positions are numbered from 1 to 8
and the "interpyrrolic" methine positions, usually called
"meso", are designated a, B, y and 6. The rings are
usually lettered A, B, C and 0, although Roman numerals were
preferred in some earlier texts. In this thesis, we chose
to use the Fischer system to name the porphyrins.

There are four possible arrangements of the two
different side chains; two of them are naturally occurring
uroporphyrin I with A,P; A,P; A,P;, A,P and uroporphyrin
III with A,P; A,P; P,A; A,P; (A = carboxymethyl and P = 2-
carboxyethyl). When three different types of substituents
are present (four of one kind, and two pairs of others) then
fifteen isomers are possible. For detailed discussion, see

the Fischer's classical work "Die Chemie des Pyrrols."

 

 

 

11

 

 

 

 

 

 

 

 

 

 

 

 

O
7 Y
A
A
l
-—A P— —-P P-
--p P --P P
I
A
' . 1-4.

 

 

Isomers of Uroporphyrin.

CHAPTER 2
SYNTHESIS OF PYRROLES AND PORPHYRINS

Introduction

 

Strategically, the synthesis of stacked-porphyrins is
best achieved by a modular approach. Individual porphyrins
are synthesized first, functional groups are introduced to
the two substituted side chains and the two chains can then
be condensed with another bifunctional molecule. Porphyrins
having difunctional groups as carboxy or amine groups are
required for the synthesis of diporphyrins which are linked
by amide bonding.

Preparation of the desired B-linked face-to-face dimer
requires the synthesis of monomeric porphyrins with suitably
functionalized side chains at positions 1 and 5 (see Chapter
1). Dialkyldeuteroporphyrin II is chosen for elaboration
mainly because of its high solubility in organic solvents,
which is essential for successful coupling and purification
of the diporphyrins or other cyclophane porphyrins. Such
type II substituted porphyrins are available by using
variations of Fischer's original dipyrromethene route [6].

Traditionally the yields of porphyrins obtained by
Fischer's method are low, but Smith [11] recently reported
that 5-methyl-5'-bromodipyrromethenium perbromide 1 gives

high yield (40-60%) of type I porphyrin when refluxed in

12

13
anhydrous formic acid, and further noted that small amounts
of water partially diverted the reaction to biliverdins of
head-to-head symmetry. It was found [13] that the carboxy-
dipyrromethene 2b, which is more conveniently prepared than
the unsubstituted analog 2c, can be brominatively decarboxy-
lated and cyclised, without isolation, to porphyrin with

equally good yield.

 

2a X=Br RI=EtL
b X=CO0H, R2=P
c X=H

 

Monomeric porphyrins with dicarboxylic ester side
chains can be converted into diamines and diacid chlorides
(see Chapter 3) which are then coupled to give the dimers
under high dilution condition [14].

For the preparation of the "slipped dimer", porphyrins
with 5,8 disubstituents are necessary. These porphyrins can
be obtained by the reaction between 5,5'-dibromodipyrro-
methenes and 5,5'-dimethyldipyrromethenes, to give porphyrins
of type II, III or IV symmetry (see Chapter 1). Using this
approach, porphyrins substituted with one to four functional
groups can also be obtained. The single functionalized

porphyrin can be used to couple an imidazole or a quinone

14
moiety for the purpose of oxygen binding or photosynthesis
model studies. This approach to porphyrin synthesis is
especially useful in that both precursors are readily avail-

able form the 5-methylpyrrole-Z-carboxylate ester [15].

Results and Discussion

 

I. Pyrrole synthesis

 

Most of the pyrroles required in our porphyrin synthesis
were S-methylpyrrole-Z-carboxylate esters. The preparation
follows the established method [7] of the Knorr—type conden-
sation of benzyl oximinoacetoacetate and 3-substituted
2,4-pentanedione 3. 2,4-Pentanedione derivatives can be
obtained by condensation with alkyl halide or by Michael

addition with methyl acrylate. 3-Pentyl-2,4-pentanedione

C H I
o o 5 " o o
0 K O
M + / Me 2C 3
I Acetone
R
Cl CH2 C025? R
3 a C5H11
b CHZ-CHZ-COOMe
c CHz-COOEt

3a can also be prepared by the hydrolysis of the BF: complex
[16] from the condensation of acetic anhydide and

2-octanone. Through the same procedure,

15
3-ethyl-2,4-hexanedione 3d was obtained from propionic an-
hydride and 2-pentanone. Pyrroles 1 were obtained in 40-50%
yield when 3-alkyl-diketones condensed with benzyl oximino-

acetoacetate in acetic acid use zinc powder as reduction

 

 

agent.
0
'0' N g R‘ 8‘73—>
/C\/R' * Rf—C—O
F\B/F o O
o/ ”"10 NoOH/Hzo 1.! I!
| u -)> CH3/ \(E/ \R2
C
1430/ §?/C\R‘ . R'
R' R1 R2
3 a CSH11 CH3
b Et Et
RI R8
8 Zn
3 + Hac-c—c-coo 821 W / \
Non ° H30 :3 c0252:
R1 R2
4 a C5H11 CH3
b P CH3
c A CH3
d Et Et

16
The hexyl side chains was introduced to 4e by Friedel-
Craft acylation in the presence of SnCl4, followed by diboran

reduction of the resulting carbonyl pyrrole 5 to obtain 6.

 

 

o
H cocn .
/\ :1" ,c.....,\
N c0232: c1, N c0232:
H 90% H
4e 5
C6
NoBH4/BF3> / \
6

The ethoxycarbonylmethyl pyrrole was reduced with
diborane to form Z-hydroxyethyl pyrrole 7 [17] and then
converted to 2-chloroethyl pyrrole 8 by thionyl chloride
[18].

17

 

510 HO
N 8H 1
o / \ a I > / \
:2 (33282] :: (Ikflmfl
4c 7
CI
2.092., / \
N C0232I
H
8

In dilute dichloromethane solution sulfuryl chloride
smoothly brought about dichloroination of the 5-methyl group
without attack on other positions. Hydrolysis then afforded

the pyrrole aldehyde in good yield.

R R
I SO
I 202

/\ 211120 /\

:11 c0232: 90 ~98 % 0Hc N €02le
H

 

R
9 a Hexyl
b Pentyl

18
Hydrogenolysis of the pyrrole benzyl esters was conducted
in THF with 10% Pd/C catalyst. When hydrogen uptake was
complete (3-24 h) the THF solution of pyrrole carboxylic
acid 10 or 11 was filtered from the catalyst and evaporated
to dryness in vacuo. Recrystallization was unnecessary; the
acids may be stored in the refrigerator for several months

without significant decomposision.

11. 92h (Type II) Porphyrins Synthesis

Czh porphyrins were obtained by the condensation of
suitable pyrroles, in the strongly acidic media, with the
pyrrole aldehyde to afford the intermediate dipyrromethenes.
Brominative decarboxylation and cyclization of dipyrro-
methenes without isolation of any of the intermediates then
afforded the desired porphyrins with very good yield. This
method is especially attractive in that the cyclization can
be performed in large scales (0.2 mole) and suffers no
decrease in yield. The porphyrins listed in Table 2-1 have
been prepared and the yields are quoted for the crystalline
products.

Small amounts of tripentyl, trihexyl and trichloro-
ethyl porphyrins 13, 14 and 15 were found in the synthesis
of 12d, 12a, and 12e. These side products may come from the
self condensatiOn of 10 or 11 during the porphyrin synthesis.

The structure of 13 can be determined by C-13 nmr.

 

19

 

 

 

 

b
12
Table 2-1. Czh Porphyrins.
R1 R2 yield (75)
10a+11a=l2a hexyl A 16
10a+11b=12b hexyl P 20
10b+11a=12c pentyl A 15
10b+11b=12d pentyl P 20
10c+11d=12e C-C-Cl A 10
12f octyl P
12f octyl A

20

III. Synthesis of porphyrins with one, two (C2 v), three and four

 

canoxyTic ac1d side chains

 

A. Synthesis of symmetrical dipyrrolmethenes:

 

(i) 5,5'-Dimethyldipyrromethenes

 

The symmetric 5,5'-dimethyldipyrromethenes were obtained
from the self-condensation of a-free acid pyrroles to give

the dipyrromethenes 16.

 

 

N COOH HCOOH
Fl
16
R1
16a A
16b P
16c C-C-Cl

(ii) 5,5'-Dibromodipyrromethenes

 

5,5'-Dibromodipyrromethenes 19 were obtained in several
steps from corresponding pyrroles. 5-Methyl pyrroles were
treated with lead tetracetate in acetic acid to give the
acetoxy methylpyrroles 17, which were then heated on a steam
bath in acidic alcoholic solution to yield the dipyrro-
methanes 18. Dipyrromethanes upon catalytic hydrogenolysis,
provided the very insoluble 5,5-dicarboxy-dipyrromethanes.
Addition of this diacid to a formic acid solution with

excess of bromine brought about rapid oxidation and

21
bromination before acid-catalysed rearrangement or decomposi-
tion [19]. The products 19 (which may be obtained as per-
bromide salts) can be converted to the bromide salt by treat-

ment with cyclohexene in dichloromethane [15].

I? [he F? IR; -, -
2‘1 - ...... » 21 L'
N c0251, CH3c00H AcOCHz N c0211; 0.,on
H

 

 

H
I?
R1 R1 R. R.
R; I \ /_ R2 I) Hzlpd/C J name,
R302C NH N COZRS 2) Bra/HCOOH Br Ngrp— Br

l8 l9

R1 R2 R3
a Et Et Et
a' Et Et 821
b P Me 821
c C-C-Cl Me 821
d hexyl Me B21
e pentyl Me 821

22
B. Synthesis of unsymmetric 5,5'-dimethyldipyrromethene

In order to make anunsymmetric porphyrin, at least one
of the dipyrromethene should be unsymmetric.

The ethyl ester pyrrol 20 was saponified with sodium
hydroxide, then neutralized with acetic acid, followed by
steam distillation. The a-free pyrrole 21 in the distillate
was immediately dried, and formylated with an excess of
phosphorus oxychloride in N,N-dimethylformamide. After
hydrolysis of the iminium salt, the aldehyde 22 was obtained

in moderate yield [1].

 

 

l) NaOH
I \ mm A T l \
N cogs: “9 H
H H
20 2!
I) FKXJ3
DMF
* \
2) NOOH N CHO
H
22

The a-free propionic acid pyrrole 23 was prepared by
hydrogenolysis of pyrrole benzyl ester, and dry distillated
vacuum. The aldehyde 22 and a-free pyrrole 23 was condensed
in methanol with 48% HBr to form the unsymmetric dipyrro-

methene 24.

23

 

 

P UH / /c P
A 2 pd 7’ H
Al Cfikflizl 29 [S A] Pi
H H
36 23
22 + 23 HBr 9
CH30H

 

C. Synthesis of porphyrins

The condensation step was carried out in a manner
similar to that reported previously [15], only one equival-
ent of bromine in formic acid was used. The mechanism of
the reaction is still unclear. The porphyrins and their
yield were listed on Table 2-2.

Instead of using bromine, saturated HBr-formic acid
solution was also effective to bring about dipyrromethene
condensation. This can be shown the porphyrin 26d in 30%
yield. The tetracarboxylic porphyrin was obtained in self-
condensation by 5,5'-dimethyl dipyrromethene in bromine or
5,5'-dibromomethyl dipyrromethene in HCl solution, but the

yield was very low (only 4%).

19a+24 =263
19a+16b=26b
19a+16b=26c
19d+16b=26d

19d+16a=26e
19h+24 =26f
19b+16c=16g
19c+16b=26h
26i
26j
16b+16b=26k
261
26m
25n
260

24

Table 2-2

 

R1

'U>'U'U

Et
EtCl

Vinyl
P
P

.A

Et
Me
Me

* in HBr/HCOOH

R2

Me
Me
Me
Me

Me
Et
Me
Me

Me
Me
Me
Et
C8
C5

Et
Me
Me
Me

Me
Me
Me
Me
Me
Me
Me
Me
Et
C8
C5

R4
Et

EtCl

Vinyl

Et

Me
Me

R5

Et
Et
Et
Me

Me
Me
Me
Me
Me
Me

Me
Me
Me

R6

Et
Et
Et
C6

C6

EtC1
Vinyl

Me
C5

Me

R7

Et
Et
Et
C6

C6

EtCl

Vinyl

R8

Et
Et
Et
Me

Me
Me

%

31
24

3O
44*

10
4O
28
23

25

 

- \
3W2 . 7“ \\ p
,
._________—9 l’ \\ :: fir
Brflzc BF CH,Br
25
A A
26k

The 2.chloroethyl porphyrin 261 and 26j can be readily
converted into vinyl groups by elimination under base condi-
tions [20]. The iron complexes derived from these synthetic
porphyrins can be combined with globin and other apoproteins.
Reconstitution experiments with these hitherto unavailable
hemes would shine light on the heme structure-enzyme function

relationship of hemoproteins [2l].

26

IV. C-13 Nuclear Magnetic Resonance of Porphyrins

 

The C-13 nmr spectra of porphyrins [22] and other
related compounds [23] are of considerable current interest.
The studies concern the electron delocalization pathway in
the porphyrin ring [24], pathways of biosynthesis [25] and
mechanisms of unpaired spin delocalization in paramagnetic
metalloporphyrins [26]. All previous C-13 nmr studies have
dealt with natural occurring porphyrins, such as copro-
porphyrins, deuteroporphyrin-IX [27] and protoporphyrin-IX
[28]. The only synthetic porphyrins previously studied
were octaethyl porphyrin and tetraphenyl porphyrin [27].

We have recorded natural abundance C-13 nmr spectra of
porphyrins with Czh and sz symmetry as well as many other
compounds. The complete spectral assignments for the C-13
nmr spectra of porphyrins were presented in Table 2-3.

(i) The assignment of a-carbon chemical shift

 

The a-carbons were found in the region between 143 to
147 ppm. The broadening of the signal was caused by the
N-H tautomerism of the porphyrin ring [29]. The a-carbons
appeared as sharp signals in the spectra of free base
porphyrins dissolved in trifluoroacetic acid and of the Zn
and Th complexes.

(ii) The assignments of B-carbons

 

The B-carbons appeared as sharp resonances between
130-140 ppm. The B-carbons in previous reports [27] were
separated into those bearing methyl, propionic ester, and

ethyl substituents. In the case of coproporphyrins the

27

oo.¢_

no.¢_

no.- no._n

n~.e—

cc.- cm.—n

n10

-.¢_

010

nn.o~

o~.-

O—.v_

nn.an

un.-

o_.c—
n10

oo.a~

om._n

oh.nu

mo.o~

no..n

ms.-
«nu

mewgagacom

aa.a~

co.m~

~—.~n

mo.a~

oo.o~

c—.mn
n10

oo.~n

om.—n

mw.~n

mo.nn

no.~n

_n.~n
«nu

nn.o~

a—.c~

o~.o~

0m.o~

sm.c~
.10

nN.Nn

m~.~n

m~.~n

nn.~n

oo.~n

NH._n
mxuo

on.Nn—

_n.~n~

nm.~n_

no.nn_

30.nn—

nu.nn—
cu

oo.Nn

n¢.~n

No.~n

c_.nn

m~.~n

o_.~n
N=u

~o.-

no.-

oo.-
~=o

oo.-
on.-
on.__
o«.—«

n¢.~_
«n._~

NR...

oo.-

o~.~.
«so

osom we came «:2 mfiuu

no.0o

an.om

on.o¢

o~.om
no.0a

c_.oo
n¢.co
5N.oo
no.co

Ola

on.nn~

m~.nn~

oo.mn_

oc.qm_

c4.¢n~

-.¢n_.

no.qn~

mn.nn—

mn.~n_

mn.~m_

o~.hn—

n¢.~n—
LI§U

.mnm mpnmh

c_.mn~
vo.o«—
.m.mn_
on.mn~

ao.on~
ma.on_

-.mn_
nm.an_

.o.on_
oo.om.
_~.an.
mo.an.
«slew

co.0n_
_0.0n_
mo.oc~
Nn.om_
oo.mn_
.o.mn_
on.o¢_
on.on~
ao._¢_
on.~q~
mo.o¢—
~o.c¢_
cc.—q~
no.5q_
mm.oe_
No.no—
o~.~q—
nu

w~_

um—

on—

an.

vu-

no

oo.v—

oo.- oo.~n

N~.e_

c—.c—

010

~_.o~ cm.-
an.o~ on.a~ 00.0n
o_.¢— n~.- o~.~n

c~.- mm.—n o~.o~

~s.- No.Nn nm.¢~

n10

no.~_

an.~n

No.“—

¢c.nn

~c.o_

cc.”—

s~.~n

——.nn

m~.nn

oe.c—
~10

so.o—

n¢.o~

o~.o_

e¢.o~

n~.o_

so.o_

n¢.o~

ne.on

on.o~

o~.a~
~10

o~.~n

_~.~n

no.~n

ao.-n

no._n

co._n

ou.~n

¢~.~n

°~.—n

no..n
nzoo

nm.nn_

_~.nn_

_o.nn_

no.nn~

on.nn_

en.nn_

co.~n_

nO.Nn~

no.n~—

on.n-
cu

A.u.8=ouv

“a...
oc.~n so..~ Na...
~_.~n no.- on...

so...
oo.~n “a._~ as...
so.~n oo._~ n8...
oo.hn um._~ No...
oo.on ha._~ ~o.__
oa.~n on...

~n...

no.~n o~.__
hm...

oo.~n ea._~ .h...
co.na ca._~ an...
:8 $6 :6

m-~ a_nah

n~.oo
~m.¢@

_N.co
no.00
n_.ca
va.co
o..om
_o.ea
no.oo
No.0a

m~.oo
o—.om
oosno
~n.oo
no.00
On.oa
NN.om
so.oa
nN.oo
nm.om

Gaul

n_.~q_

mo.qm_
cm.¢n_
O~.~ed
o~.~e—
an.nn_

mo._¢_

m~._c~
Na.wn_
n~.nn—
n~.nn—
o~.~¢~

«o..e_
1:268

an.mm_

~c.mn_
n—.mn—
‘~.mm_
n~.on_
o~.sn_
«n.0n—
~m.om-
o~.~n_
~Q.Om_

aw.sn~

0Q.Nn—
QIQU

No.qn_
no.om_
4=.c..
cc.cn_
m_.oc_
en._c_
~_.nn_
m~.on_
m_.on_
No.cc_

n_.on~

no.nn_
co.on_
Oo.~n—
~a.04_
nm.~n_
co.c¢_
a~.on—
uo.oc—

c_.on_
u:-uu

na.ec~
nm.~c—
nm.nc_

o_.o¢_
«w.~¢—
—_.nc_
ow.¢c_
n~.mc_
on.¢e_

o~.¢¢_
oo.~¢_
o~.nv—
oc.oq_
«o.n¢d
_o.¢¢~
3.3:
cm.¢¢—
o¢.nn_
ma.c¢~

o..eq.
no

0“ am

cuaou

nu

0am:

co~

sow

oo~

noN

voN

new

29
CB-Me's were assigned to higher field, around at l36 ppm by
comparison with toluene (C4 = l37.3 ppm). The CB-P shifts
were assigned to lower field at 138 ppm (C-1 of methyl-3-
phenylpropionate = 140.1 ppm).

From the B-carbon chemical shifts of the compounds shown
in the Table, the CB-Me were separated into two groups, those
with a P or A chain on the same pyrrole ring, and those with
an alkyl group on the same ring. The chemical shift of CB-Me's
of proto- or deuteroporphyrin cannot be applied to these com-
pounds. From the data in the Table, we assigned the chemical
shift by their substituent environment. Those CB-Me's bet-
ween P (or A) and alkyl groups appeared in the 140 ppm
region, but the CB-Me between P (or A) and methyl or P and P
Q6f)appeared at 136i1 ppm. From the chemical shift of CB-Me
we can determine the environment of the CB-Me. The CB-P
appeared around the 137-138 ppm region as reported with Czh
symmetry compounds. In porphyrins with sz symmetry such as
26e, 26f the CB-A were shifted to high field by about 3 ppm
to 130 ppm. The assignment of the CB-A was based on the
similar analogous C-1' of methyl phenyl acetate at 134.4 ppm.
The CB-alkyls appeared in the 133-134 ppm region for the Czh
compounds, and at 165 ppm region for sz compounds. The C8-
ethyl were found around 141-142 ppm by comparing with meso-
and deuteroprophyrins.

(iii) The meso carbons

 

The meso-carbons were assigned unambiguously from the

literature [27] in the region around 96 ppm. The environment

30
of the mesa-carbon has little effect on their chemical shift.
The splitting of meso-carbon signals were dependent on the
symmetry of the molecule. Compounds 12c, 12f, 129 as well as
coporporphyrin and deuteroporphyrin exhibited only one meso
signal.

(iv) The methyl carbons

 

The methyl group chemical shift appeared at 11-12 ppm as
reported in the literature [27]. In compounds 12b, 12d, and
12f, there was only one methyl signal, in spite of the
difference of these two symmetry.

(v) The methyl propionate and acetate carbons

The assignment of the methyl propionate was based on the
literature [27]: C—1' (22 ppm); C-2' (37 ppm); carbonyl
(I73 ppm);methoxy (51 ppm). There was no report about the
acetate. From the chemical shift of the methyl phenyl
acetate [30], C-15 was assigned at 41.1 ppm, the C-1' of
acetate of porphyrin derivatives was assigned at 32 ppm. The
10 ppm difference of the porphyrin andbenzenenucleus was
also evident in the propionated 21 ppm in porphyrin and 31
ppm in benzene.

(vi) The alkyl groupycarbons

 

The assignments of alkyl carbons were based on the
literature [31]. Long chain alkyl carbons were assigned on
the basis of benzene analogues and octaalkyl .porphyrins.

The assignment of the B-carbons in the porphyrins were‘
very difficult, only a few simple porphyrins have been

assigned completely. We assigned the synthetic porphyrin

31
B-carbons based upon their substituent environment, from
this, it is also possible to determine the structure of
porphyrin.
(vii) Structure determination of porphyrin side product

by C-13 nmr

 

A side product was obtained during the synthesis of
porphyrin 12d. The structure of this compound was proved to have
one methyl propionate ester and three pentyl side chains by pmr
and the mass spectrum. However the relationship between these
side chains and the four methyl groups could not be elucidated
from pmr. The C-13 nmr of 13, measured in CDCl3 showed that
the CB-Me's have chemical shifts at 141.34, 140.18, 136.66,
136.04 ppm. From the C-13 chemical shift data obtained from
known porphyrins discussed previously, the signals were
assigned as below.

The two peaks at 140.18 and 141.34 were assigned to be
the CB-Me between pentyl and pr0pionate, the two signals at
136.66 and 136.04 belonged to the CB-Me between methyl and
pentyl. From the arrangement of these four methyl groups,

the structure of 13 can be elucidated.

 

32
The north hemisphere then must be from the original
dipyrromethene, the other dipyrrolemethene arises from the

head to head condensation of two C5 pyrroles.

Experimental

 

Reagents and Solvents

 

All solvents and reagents were of reagent grade quality,
purchased commercially, and used without further purification
except noted. Methylene chloride was distilled from calcium
hydride. Suifuryl chloride was redistilled. Silica gel for
column chromatography (60-200 mesh) was from J. T. Baker
(3405). Preparative silica gel plates were from Analtech,
Inc. For analytical TLC, Eastman 13181 chromatography sheet
was used.

Physical and Spectroscopic Methods

 

Melting points were obtained on an Electrothermal
melting point apparatus and are uncorrected. Visible spectra
were obtained on a Cary 17 or 219 spectrophotometer. The
infrared spectra were recorded on a Perkin-Elmer Model 237 B
spectrophotometer. The PMR spectra were obtained on a Varian
T-60 and Bruker WM250 spectrometer with chemical shifts re-
ported in 6-units measured from tetramethylsilane as the
internal standard. A Varian CFT-20 spectrometer was used for
C-13 NMR spectra. Mass spectra were obtained in a Hitachi
Perkin—Elmer Instrument RMU-6 mass spectrometer and Finnigan
4000 GC/MS system using the direct inlet mode, at 70 ev
ionization energy. Field absorption mass spectra were

obtained from Varian CH-5 mass spectrometer. Elemental

33
analyses were done by Spang Microanalytical Laboratory,
Eagle Harbor, Michigan.

General procedures for the synthesis of 3-alky132,4-

 

pentanedione, 3-Ethyl-2,4-hexanedione-BF2 Complex

Boron trifluoride gas was slowly bubbled through a
mixture of 2-pentanone (43 g, 0.5 mol) and propanoic anhydride
(130 g, 1.0 mol) in such a manner that the temperature of the
mixture was kept below 50°C. After the absorption of boron
trifluoride has ceased the mixture was poured into ice/water
(500 ml). The solid product was collected by filtration and
recrystallized from methanol; yield: 85 g (89%); m.p.
75-77°c; p.m.r. 1.08 (t, a = 3 Hz, 3H), 1.22 (t, J = 8 Hz,
3H), 2.32 (s, 3H), 2.33 (q, J = 8 Hz, 2H), 2.60 (q, J = 8 Hz,
2H).

 

3-Ethyl-2,4-hexanedione 3d

3-Ethyl-2,4-hexanedione-BF2 complex (11 g) was dissolved
in methanol (50 ml). This solution was brought to PH 9 by
adding 50% aqueous sodium hydroxide. The mixture was
refluxed on a steam bath for 15 min, methanol was removed in
a rotary evaporator, and the residue was taken up in ether
(50 ml). The solution was dried with sodium sulfate, the
ether evaporated, and the residue distilled; yield: 6.5 g

(80%); b.p. 191-1930C; p.m.r. 0.37 (t, J = 7 HZ, 3H), 1.02

(t, J

(q. J
15% of 1H).

7 Hz, 3H), 1.80 (t, J 7 Hz, 2H), 2.08 (s, 3H), 2.44

7 Hz, 2H), 3.52 (t, J 7 Hz, 1H), 16.3 (s, broad,

34

 

3-Pentyl-2,4-pentanedione BF2 Complex

This compound was prepared as above, b.p. 155-1570/2
mmHg; p.m.r. 0.9 (braod, 3H, -(CH2)4-Cfl3), 1.33 (broad, 6H,
-(§H2)3-CH3), 2.20 (t, J = 8 Hz, 2H, ~0H2-C4H9), 2.30 (s, 6H,
-CH3).

3-Pentyl-2,4:pentanedione 3a

 

3a was obtained as above, b.p. 123-1250/20 mmHg; p.m.r.

0.87 (broad. 3H, -(CH2)4-Cfl3), 1.26 (broad, 6H, -CH2-(£H2)3-

CH3), 1.67-2.00 (broad, 2H, ~2H2-C4H9), 2.17 (S, 6H, -CH3),
3.57 (t, J = 7.0 Hz, methine proton), 16.3 (s, enol form,
-0H).

Ethyl-3-acety]-4-oxop§ntanoate 3c

 

Ethyl chloroacetate (551 g) was added slowly to a stirred
mixture of acetylacetone (450 g), anhydrous potassium
carbonate (570 g), and dry acetone (500 ml). During the
addition the mixture was heated to reflux. When all the
acetate was added, the mixture was kept refluxing for a
further 1 hr. The mixture was filtered when cool, and the
acetone removed under reduced pressure. The residual oil was
fractionated twice under vacuum. Yield: 500 g (60%); b.p.
110-5°/o.1 mmHg; p.m.r. 1.27 (t, J = 7.0 Hz, -CH2£H3), 2.17

(s, -CH3 enol form), 2.27 (s, -CH keto form), 2.86 (d, J =

3

7.0 Hz, -§fl2-C00Et, keto form), 3.25 (s, ~CH ~CO0Et, enol

2
form), 4.10 (t, J = 7.0 Hz, methene proton), 4.13 (q, J =

7.0 Hz, -CH2CH3). The ratio of enolzketo = 1:3. M+ = 186.

35

The general procedure of the synthesis of pyrroles (4a-e)

Benzyl-3,5-dimethylpyrrole-2-carboxyjate 4e

1030 g (5 mol) of benzyl acetoacetate [32] in 1080 g
(18 mol) acetic acid were kept at room temperature with
stirring, 1242 g of sodium nitrite in 1560 ml water were
added through a peristatic pump into the acetic acid
solution during 20 hrs. After the addition, the upper
(organic) layer of benzyl oximinoacetoacetate was separated,
no further purification was necessary.

In a three neck 12 l round bottom flask equipped with
mechanical stirrer, 6 moles of diketone and 3000 ml acetic
acid were added. The benzyl oximinoacetoacetate was slowly
added to the flask by a pump while 200 g of zinc dust were
added gradually. The temperature rose to around 90-950C.
More zinc dust was added during the reaction to keep the
temperature at 90-950C. After the reaction was over (6 hrs),
excess zinc and zinc acetate was allowed to precipitate. The
brown liquid, still hot, was decanted to a bucket containing
10 l water. After cooling the product of pyrrole was
collected by filtration and washed by water. The solid was
dissolved in methylene chloride and filtered. The methylene
chloride solvent was removed under reduced pressure. The
pyrroTes were recrystalized from methanol to give a slightly
yellow crystal; p.m.r. 2.2 (s, 3H, CH3), 2.3 (s, 3H, CH3),
5.2 (s, 2H, QHZB), 5.7 (broad, 1H), 7.2 (s, 5H, phenyl protons).

36
Benzyl]4-pentyl-3,5-dimethylpyrole-2-carboxylate (4a)
M.P. 65-660C; p.m.r. 0.83 (broad triplet, 3H, -CH3),
1.27 (broad, 6H, -CH2-(£H2)3-CH3), 2.10 (s, 3H, -CH3), 2.20
(s, 3H, -CH3), 2.20 (broad, 2H, -£H2—C4H9), 5.17 (s, 2H,
-CH3), 7.20 (s, 5H, -8), 8.50 (broad, 1H, -NH). M+ = 289.
Benzyl 4-methylcarboxyethyl-3,5-dimethylpyrrole-2-
carboxylate [33] 4b

Yield: 47%; m.p. 96-980C.

 

Benzyl 4-ethylcarboxymethyl-3,5-dimethylpyrrole-2-

carboxylate 4c

 

Yield: 45%; m.p. 74-76°c.

Benzyl 3,4-diethyJ-5-methyl-2-carboxylate [34] 4d
Yield: 43%; m.p. 72°C.
Benzyl4-(1-oxo-hexane)-3,5-dimethyl-2-carboxylate-
pyrrole 5

 

57.3 g of pyrrole 4e was dissolved in 300 ml dry methyl-
ene chloride. This solution was cooled to 10°C in an ice
bath and 35 ml of hexanoyl chloride was added. To this
mixture 40 ml of SnCl4 was added dropwise through a pressure-
equalizing dropping funnel. The reaction temperature was
kept below 15°C. After all SnC14 was added, the mixture was
kept stirring for 1 hr in the ice bath. A sample was with-
drawn and mixed with 2 ml of methylene chloride and 10 ml
water. The organic solution was spotted on silica gel TLC
and developed in CHZClz. When there was no starting material
left, the reaction mixture was poured into 200 ml of cold

water, the organic layer was separated and washed twice with

37
sodium carbonate solution, and water. The solvent was
removed under reduced pressure. A white crystalline solid
was obtained after recrystalized in methanol; m.p. 86°C;
p.m.r. 0.87 (broad, 3H, -CH3), 1-00-1.60 (broad, 6H, -CH2-
(CH2)3-CH3), 2.43 (s, 3H, -CH3), 2.56 (s, 3H, -CH3), 2.67 (t,
J = 7.0 Hz, 2H, -§H2-C0-), 5.20 (s, 2H, ~0H20), 7.23 (s, 5H,
phenyl protons), 9.00 (broad, 1H, -NH).

Benzyl 4-heny-3,5-dimethylpyrrole-Z-carboxylate 6

 

In a 250 ml flask, 32 g of pyrrole 5 was dissolved in
100 ml THF, 8 g of sodium borohydride was added. The mixture
was cooled to 10°C with stirring in an ice bath. To this
mixture, 35 ml of trifluoroborane-etherate was added dropwise
such that the temperature of the mixture was below 15°C.
After the addition of BH3 was completed, the mixture was kept
in ice bath for another 2 hr. The mixture was poured into
200 ml ice water, 50 ml concentrated HCl and 200 ml chloro-
form were added. The organic layer was separated and washed
first with 200 ml 0.5 N HCl, then water. 50 ml of methanol
was added to the methylene chloride solution before it was
evaporated to dryness. The residue was recrystalized with
methanol to afford pyrrole 13.5 9 (yield 43%); p.m.r: 0.87
(broad, 3H, -(CH2)5-gfl3), 1.33 (broad, 8H, -CH -(£H2)4-CH3),

2

2.13 (broad, 2H, -Qfl2-C5H11), 2.16 (5, 3H, -CH3), 2.27 (s,

3H, -CH3), 5.20 (s, 2H, -CH20), 7.23 (s, 5H, phenyl protons),
8.50 (broad, 1H, NH).

38
Benzyl 4-(2-hydroxyethy])-3,5-dimethylpyrrole-2-

 

carboxylate 7

 

Benzyl~4-(2-methoxycarboxymethyl)-3,5-dimethylpyrrole-2-
carboxylate (5 g, 0.02 mole) was dissolved in 100 ml dry THF
and 1 M solution of borane-tetrahydrofuran complex 50 ml was
added dropwise during 45 min. Methanol was then carefully
added until the vigorous reaction ceased. The solvent was
removed on a rotary evaporator, and the hydroxyethylpyrrole 7,
4.5 g (99%) was crystallized from benzene-petroleum ether to
give white needle; m.p. 120-1210C; p.m.r. 2.16 (s, 3H, -CH3)

2.23 (S, 3H, -CH3), 2.60 (t, J = 7.0 Hz, 2H, -£H -CH2-0H),

2
3.71 (t, J = 7.0 Hz, 2H, -CH2-£H2-OH), 5.23 (s, 2H, -QH20),
7.27 (s, 5H, phenyl protons).

Benzyl 4-(2-chloroethyl)-3,5-dimethylpyrrole—2-

 

carboxylate 8

Benzyl—4-(2-hydroxyethyl)-3,5—dimethylpyrrole-Z-carboxy-
late 7 (2.8 g) in 20 ml dry methylenechlordie and 1 ml
pyridine was heated at 50°C, 1 ml thionyl chloride was rapidly
added. Dry nitrogen was then passed through the solution at
50°C for 1 hr. 100 ml of methylene chloride was added and the
solution washed with 2N HCl, saturated aqueous sodium bi-
carbonate solution, and then water. The organic layer was
dried over sodium sulfate and evaporated to dryness. The
residue was recrystallized from methanol to give 8 (2.5 g,
84%); m.p. 120-12100. p.m.r. 2.17 (s, 3H, -CH3), 2.23 (s,
3H, -CH3), 2.77 (t, J = 7.0 Hz, 2H, -Cfl2C1), 3.43 (t, J = 7.0
Hz, 2H, ~9H20H2-c1), 5.17 (s, 2H, ~9520), 7.22 (s, 5H, phenyl
H), 10.90 (broad, 1H, NH).

39

Benzyl 5-formyl-4-hexyl—3-methylpyrrole-2-carboxylate 9a

 

Pyrrole 6 (23 g) was dissolved in 250 ml dry methylene
chloride and 21 g of sulfuryl chloride in 200 ml dry methylene
chloride was added to the stirring pyrrole solution at 0°C in
an ice/salt bath. The addition of sulfuryl chloride took
about 4 hr. After completion of addition, the solution was
stirred for additional 30 minutes at room temperature, and
300 ml 50% aqueous methanol was added and the mixture was
stirred overnight. The organic layer was separated and
reduced to 200 ml. The brown solution was shaked with l00
ml 50% aqueous methanol, the methylene chloride layer was
separated and washed with sodium bicarbonate solution, then
washed with water. Evaporation of the solvent afforded a
brown oil which solidified on standing, the solide was
recrystallized from 95% MeOH to give a pale yellow product.
p.m.r. 0.83 (broad, 3H, -CH3), 1.30 (broad, 8H, -(CH2)4-CH3),
2.27 (s, 3H, -CH3), 2.67 (t, J = 7.0 Hz, 2H, -CH2-C5H11),

5.27 (s, 2H, -CH20), 7.33 (s, 5H, phenyl protons), 9.70 (s,
1H, aldehyde proton). m.p. 55°C.

Benzyl 5-formyl-4-pentyl~3-methylpyrrole-Z-carboxylate 9b

This compound was obtained using the procedure for 9a.

p.m.r. 0.83 (broad, 3H, —CH3), 1.33 (broad, 6H, -(CH -CH3),

2’3

2.23 (s, 3H, -CH3), 2.67 (t, J = 7.0 Hz, 2H, -£H2-C4H9), 5.27

(s, 2H, -£H2-0), 7.24 (s, 5H, phenyl protons), 8.70 (broad,

1H, NH), 9.60 (s, 1H, aldehyde proton). m.p. 62-630C. M+ =

313.

40
Benzyl 5-formyl-4-methoxycarbonylethyl-3-methylpyrrole—

2-carbonyate 9c

 

This compound was obtained as above, p.m.r. 2.27 (s, 3H,
-CH3), 2.50 (t, J = 6.0 Hz, 2H, -£H2-COOCH3), 3.00 (t, J = 6.0
Hz, 2H, -§fl2-CH2-C00CH3), 3.57 (s, 3H, 0CH3), 5.23 (s, 2H, -gHzo),
7.23 (s, 5H, phenyl protons), 9.67 (s, 1H, aldehyde proton). m.p.
75°C. M+ = 329.

Catalytic hydrogenolysis of benzyl esterypyrroles or

dipyrromethanes

 

The identical procedure was used for all benzyl esters. The
appropriate pyrrole ester (0.1 mol) was dissolved in 200 ml dry
THF and a few drops of triethylamine and 1 g of 10% palladized
charcoal was added. The mixture was stirred under 1 atm of
hydrogen until hydrogen uptake had ceased (3-24 hr). The fil-
trated solution was evaporated to dryness in vacuo, to give the
pink pyrrole acid in almost quantitative yield. The pyrrole
acids can be stored in freezer for months without decomposition.

General synthesis procedure of the Cgh porphyrins

2-Methyl-5-carboxylic acid pyrrole 11, 15 mmol, and
5-carboaldehyde-Z—carboxylic acid pyrrole 10, 15 mmol, were
dissolved in 80 ml methanol and 80 ml acetonitrile. The
solution was heated on a steam bath for 5 min then 2.5 ml of
48% HBr solution was added. The mixture was kept refluxing
for 30 min and then evaporated under reduced pressure. The
dark brown residue was dried under vacuum overnight. The
dipyrromethene was dissolved in 15 ml anhydrous formic acid

and heated on an oil bath to 80°C for 5 min, bromine (0.9 ml,

41
20 mmol) was added slowly and the oil bath temperature was
raised to 120-1250C. The mixture was refluxed for 2-2.5 hr.
The solvent was then boiled off by blowing air into the flask.
The black residue was dissolved in 100 ml methanol and 5 ml
concentrated sulfuric acid was added, followed by 20 ml tri-
methyl orthoformate. After standing overnight, the mixture
was basified with triethylamine and evaporated to dryness.
The crude methyl esters were chromatographed on silica gel,
using methylene chloride as eluent, a dark non-fluorescent
fraction was discarded, the porphyrin fraction was concen-
trated and precipitated with methanol. Yield: 10-20% from
pyrroles. The physical properties of porphyrins are listed
below.

Porphyrin 12a

 

m.p. 208-210°c. p.m.r. 0.90 (broad, 6H, -(CH2)5-§H3),

1.50 (broad, 12H, -CH2-(§H2)3-CH3), 2.13 (broad, 4H, -QH2-

C4H9), 3.42 (s, 6H, -CH3), 3.47 (s, 6H, -CH3), 3.67 (S, 6H,

-OCH3), 3.83 (t, 4H, -£fl2-C5H 4.80 (s, 4H, -£H2-COOCH

11), 3)!
’9.70, 9.73 (s, 4H, meso protons), -3.95 (broad, NH). v15:

397, 497, 532, 566, 620 nm. M+ = 678.

Porphyrin 12b

 

m.p. 146-1480C. p.m.r. 0.90 (broad, 6H, -(CH2)5-CH3),

1.60 (broad, 12H, -(Cfle) -CH 9 2.27 (broad, 4H, -gH -c H ),

3), 2 4
-C00CH3), 3.53 (s, 6H, -CH3),

3

3.20 (t, J = 7.0 Hz, 4H, -gH2

3.56 (s, 6H, -CH3), 3.67 (s, 6H, -OCH3), 3.97 (t, J = 6.0 Hz,

4H, -gH -c H ), 4.30 (t, J = 7.0 Hz, 4H, -gH

2 5 11 2 2

10.0 (s, 4H, meso protons). VIS: 400, 498, 536, 565, 620

nm. M+ = 706.

-CH -COOCH3),

42

Pogphyrin 12c

 

m.p. 190°C. p.m.r. 0.95 (broad, 6H, -(CH2)5-CH3), 1.60
(broad, 8H, -(CH2)2-CH3), 2.17 (broad, 4 H, -CH2-C3H7), 3.17
(t, 4H, -CH2-000CH3), 3.57 (s, 6H, -CH3), 3.60 (s, 6H, -CH3),
3.63 (s, 6H, 40CH3), 4.0 (t, 0 = 7.0 Hz, -CH2-C4H9), 4.33 (t,
J = 7.0 Hz, -CH2-CH2-C00CH3), 9.93 (s, 4H, meso protons).
v15: 398, 496, 532, 566, 618 nm. M+ = 650.

Porphyrin 12d

m.p. 221°C. p.m.r. 0.93 (broad, 6H, -(CH2)4-CH3), 1.57
(broad, 8H, -(CH2)2-CH3), 2.37 (b, 4H, -9H2-C3H7), 3.43 (s,
6H, —CH3), 3.47 (s, 6H, -CH3), 3.70 (s, 6H, -0CH3), 3.83 (t,
4H, -gH2-C4H ), 4.8 (s, 4H, -£H2-C00CH3), 9 70, 9.77 (s, 4H,
meso protons). VIS: 400, 500, 516, 534, 620 nm. M+ = 622.

Porphyrin 12e

p.m.r. 3.68 (s, 12H, -CH3), 3.90 (s, 6H, -0CH3), 4.24

 

(t, J = 8.0 Hz, 4H, -CH2-Cfl2-C1), 4.56 (t, J = 8.0 Hz, 4H,
-QH2-CH2-C1), 5.12 (s, 4H, -gflz-C00CH3), 10.08, 10.24 (s, 4H,
meso protons), -4.06 (b, 2H, NH). VIS: 400, 495, 530, 565,
620 nm.

Porphyrin 13

m.p. 139-140°c. p.m.r. (250 MHz): 0.95 (t, 9H, -(CH2)4-
953), 1.55 (m, 6H, -(CH2)3-gH2-CH3), 0.70 (m, 6H, -(£flp)-
Csz), 2.28 (m, 6H, -gH2-C3H7), 3.28 (t, 2H, -CH2-CHZ-C006H3),
3.59 (broad, 12H, -CH3), 3.70 (s, 3H, 0CH3), 4.02 (m, 6H,

-£fl -C4H9), 4.40 (t, 2H, CH -CH2-C00CH3), 10.03 (s, 4H, meso

2 2

protons). M+ = 622.

43

Porphyrin 14

 

p.m.r.: 0.90 (b, 9H, (CH2)5-CH3), 1.50 (b, 18H, -(£Hz)3-

CH3), 2.23 (b, 6H, -gH -c H ), 3.5 (s, 12H, -CH3), 3.67 (s,

2 4 9
6H, -OCH3), 3.90 (b, 6H, -£H2-C5H11), 4.67 (s, 2H, ~2H2-
CDOCH3), 9.80 (s, 4H, meso protons), -3.73 (b, 2H, NH).

Porphyrin 15

 

p.m.r.: 3.64 (S, 12H, -CH3), 3.88 (s, 3H, ~0CH3), 4.24

(t, J = 8.0 Hz, 6H, —CH -£fl -c1), 4.48 (t, J = 8.0 Hz, 6H,

2 2
-£fl2CH2-C1), 5.08 (S, 2H, -Qfl2-COOCH3), 10.12 (s, 3H, meso
protons), 10.28 (s, 1H, meso proton), -4.16 (b, 2H, NH). VIS:
402, 500, 532, 568, 622 nm.

3,3'-(2-Hydroxycarbonylmethyl)-2,2',4,4'-tetramethyl-

 

5,5'—dipyrromethenium bromide 16a

 

2-Methoxycarbonylmethyl pyrrole 4c (16 g) was hydro-
genolyzed with 10% Pd/C in THF. The a-acid pyrrole was
refluxed in 100 ml formic acid plus 20 ml 48% HBr on a steam
bath for 4 hr. After cooling, 12 g (60%), 0f 16a was
obtained. p.m.r. (CDCl3/TFA): 2.33 (s, 6H, —CH3), 2.57 (s,

6H, -CH 3.57 (S, 4H, -£H2-CDOH), 7.17 (s, 1H, methine

3).
proton).

3,3'-(2-Methoxycarbonyl):2,2',4,4'-tetramethyl-5,5'-

 

dipyrromethenium bromide 16b

 

2-Methoxycarbonylmethyl pyrrole 20 g was catalytically
hydrogenolyzed to acid. After reacted with 48% HBr, 13.4 g
(99%) of 16b was obtained. m.p. 206-2070C. p.m.r.: 2.23
(s, 6H, -CH3), 2.50 (t, J = 6.0 Hz, 4H, CHZ-gflz-COOCH
2.63 (s, 6H, -CH3), 2.70 (t, J = 6.0 Hz, -CH

3),

CH COOCH

2 2 3)’

44

3.57 (s, 6H, -0CH3), 6.90 (s, 1H, methine proton), 9.63 (b,
2H, NH).

3,3'-(2-Chloroethyl)-2,2',4,4'-tetramethyl-5,5'-

dipyrromethenium bromide 16c

m.p. 217-219°C. p.m.r.: 230 (s, 6H, -CH3), 2.67 (s,
6H, -CH3), 2.93 (t, J = 6.0 Hz, 4H, -CH2£H2Cl), 3.37 (5,
J = 6.0 Hz, 4H, -§H2-CH2Cl), 6.97 (s, 1H, methine proton),
9.67 (b, 2H, NH).

5-Acetoyymethylf2-ethoxycarbonyl-3,4-diethylpyrrole 17a

2-Ethoxycarbonyl-3,4-diethyl-5-methylpyrrole 4d (20.9 g)
was dissolved in 100 ml acetic acid containing 2 ml acetic
anhydride and lead acetate (48 g) was added all at once. The
mixture was stirred by magnetic stirrer and after a brief
induction period, the mixture dissolved, reacting exother-
mically. The mixture was warmed briefly to 60°C to ensure
completion of reaction. 5-10 ml of ethylene glycol was
added to reduce any remaining lead (IV) followed by 400 ml
water. The precipitates were throughly washed with water
and filtered to yield 19.5 g solid which were pure enough
for further reactions. m.p. 70-72°C. p.m.r.1.07 (t, J =
7.0 Hz, 3H, -CH3), 1.10 (t, J = 7.0 Hz, 3H, -CH3), 1.32 (t,
J = 7.0 Hz, 3H, -CH3), 2.00 (s, 3H, COCH3), 2.41 (0, J = 7.0
Hz, 2H, -CH2CH3), 2.67 (q, J = 7.0 Hz, 2H, -CH2CH3), 4.23
(q, J = 7.0 Hz, 2H, -0CH3), 4.93 (s, 2H, -Cfl20AC), 8.8 (b,

1H, NH). M+ = 267.

45
Benzyl 5-acetoxymethyl-4-(2-chloroethyl)-3-methyl-

pyrrole-Z-carboxylate 17c

 

Lead tetraacetate 4.0 g was added in portions during 2
hr to a stirred solution of 2-Chloroethylpyrrole 2.6 g in 100
ml acetic acid and 2 ml acetic anhydride. After stirring at
room temperature overnight, water (200 ml) was added to form
precipitates. The solid was collected by filtration, washed
with water and then dried under vacuum. The acetoxymethyl-
pyrrole 17c (2.9 g, 97%) was recrystallized from methanol;
m.p. 16b-169°C. p.m.r. 2.00 (s, 3H, -CH3), 2.23 (s, 3H, -CH3),
2.85 (t, J = 7.0 Hz, 2H, -§H2C1), 3.45 (t, J = 7.0 Hz, 2H,
-CH2CH2C1), 4.93 (s, 2H, -§fl20Ac), 5.20 (s, 2H, -£H20), 7.23
(s, 5H, phenyl protons), 9.00 (broad, 1H, NH).

Benzyll%acetoxymethyl-4-hexyl-3-methylpyrrole-2-

 

carboxylate 17d

 

4-Hexylpyrrole 34 g was dissolved in 200 ml acetic acid
and 10 ml acetic anhydride. Lead tetraacetate (50 g) was
added in portions during 2 hrs. The mixture was stirred at
50°C overnight. 500 ml water was added to precipitate the
product. The solid was collected by filtration. m.p. 83-
85°C (98%). p.m.r. 0.83 (broad, 3H, -(CH2)5-£fl3), 1.27 (s,
8H, -(£fl2)4-CH3), 2.00 (s, 3H, COCH3), 2.23 (S, 3H, -CH3),
2.35 (broad, 2H, ~9H2-C5H11), 4.90 (s, 2H, -£H2-0Ac), 5.20

(s, 2H, -QH20), 7.23 (s, 5H, phenyl protons), 8.87 (broad,

NH), M+ = 371.

46

5,5'-Diethoxycarbonyl-3,3'4,4'-tetraethyl-2,2'-

 

idipyrromethane 18a

 

17a (15 g, 0.057 mol) dissolved in 95% ethanol (100 ml)
was heated to boiling on a steam bath. Concentrated HCl (1
ml) was added and the heating was continued for an hour. The
solution was then allowed to cool overnight; light yellow
chunky solid crystallized out. 11 g was collected (96%).
m.p. 84-85°C. p.m.r. 1.16 (t, 0 = 7.0 Hz, 6H, -CH2gH3), 1.30
(t, J = 7.0 Hz, -CH2£H3), 2.70 (q, J = 7.0 Hz, 4H, -gH2CH3),
3.80 (s, 2H, methene protons), 4.20 (q, J = 7.0 Hz, -COOCH2-

+

CH3), 8.58 (broad, 2H, NH). M = 402.

2,2'-Dibenzyl-3,3',4,4'-tetraethyl-2,2'-dipyrromethane

 

dicarboxylate 186'

 

11 g of 18a was added to 50 ml refluxing benzyl alcohol
under nitrogen. 10 ml of sodium benzylate solution prepared
deissolving a small piece of sodium (1 g) in benzyl alcohol
(20 ml) was added into the mixture and the refluxing was
continued for 3 hrs. The reaction mixture was cooled to about
100°C and poured into icewater (500 ml). The solid was
collected by filtration. The product of 13 9 18a' (91%) was
pure enough for further reactions. p.m.r. 0.80-1.40 (two
sets of triplet, J = 8.0 Hz, 12H, -CH29H3), 2.40 (q, J = 8.0
Hz, 4H, -£fl2CH3), 2.73 (q, J = 8.0 HZ, 4H, -£fl2CH3), 3.78
(s, methene proton), 5.20 (s, 4H, -Cfl20), 7.20 (s, 5H, phenyl
protons), 7.23 (s, 5H, phenyl protons). M+ = 526.

47

 

2,2'-DibengyI-3,3'-di(2-chloroetfly1)-4,4'-dimethyI-5,5'-

dipyrromethane dicarboxylate 18c

 

The 4-(2-Chloroethyl)-5-acetoxypyrrole 2.9 g was dis-
solved in a mixture of 100 ml ethanol and 20 ml concentrated
HCl, and the solution was heated under reflux on a steam bath
for 5 hr. After cooling,methylene Chloride (100 ml) was
added and the solution was washed first with 5% aqueous sodium
bicarbonate solution, then with water, separated, and dried
over sodium sulfate, and evaporated to dryness. After re-
crystalized from methanol, 2.35 g of the dipyrromethane 18c
(50%) was obtained. m.p. 134-135°c. p.m.r. 2.21 (s, 6H,
-CH3), 2.77 (t, J = 7.0 Hz, 4H, -CH29H2C1), 3.33 (t, J = 7.0
Hz, 4H, -§H2CH2C1), 3.77 (s, 2H, methylene protons), 5.10 (s,
4H, -Cfl20), 7.10 (s, 10H, phenyl protons), 9.70 (broad, 2H,
NH).

2,2'-Dibenzyl-4,4'-diheny-3,3'-dimethyl-5,5'-dipyrro-

methane dicarboxyjate 18d

 

m.p. 93-95°C. p.m.r. 0.87 (b, 6H, -(CH2)5-QH3), 1.32
(b, 16H, -(£H2)4-CH3), 2.20 (s, 6H, -CH3), 2.33 (b, 4H, £52-
C5H11), 3.70 (s, 2H, methene protons), 5.10 (s, 4H, -Cfl20),
7.10 (s, 10H, phenyl protons), 9.02 (broad, 2H, NH). M+ =
610.

2,2'-Dibromo-3,3',4,4'-tetraethyl-5,5'-dipyrromethenium

 

bromide 19a

 

13 g of 18a was hydrogenolyzed with pd/c catalyst in
THF as described above. A solution of bromine (10 g) in dry

formic acid (100 ml) was poured into the dicarboxylic acid

48

solution and the mixture swirled until mixing was complete.
The solution was allowed to stand overnight. The crystals
were collected by filtration, washed with ether to give pure
13 g (100%) of product. m.p. 145-147°C. p.m.r. 1.10 (t,
J = 7.0 Hz, 6H, -CH2£H3), 1.23 (t, J = 7.0 Hz, 6H, -CHZCH3),
2.43 (q, J = 7.0 Hz, 4H, -§fl2CH3), 2.70 (q, J = 7.0 Hz, 4H,
-§H2CH3), 7.10 (s, 1H, methine proton).

5,5'-Dibromo-3,3'-di(2-methoxycarbonylethyl):4,4'-

dimethyl-2,2'-dipyrromethenium bromide 19b

19b was obtained as described in reference 15.

2,2'-Dibromo-4,4'-(2-chloroethyl)-3,3'-dimethyl-545'-

dipyrromethenium bromide 19C

The compound 19c was prepared as above. m.p. >300°C.
Yield: 20%. p.m.r. (CDCI3/TFA), 2.07 (s, 6H, -CH3), 3.13
(t, J = 6.0 Hz, ~CHZQHZC1), 3.62 (t, J = 6.0 Hz, 4H, -CH_CH2-
CI), 7.20 (s, 1H, methine proton).

2,2'-Dibromo-4,4'-dihexyl-3,3'-dimethyl-5,5'-dipyrro-

methenium bromide 19d

The compound 19d was prepared as above. m.p. 198-2000C.
Yield: 53%. p.m.r. 0.87 (b, 6H, -(CH2)5-Cfl3), 1.33 (b, 16H,
-(§fl2)4-CH3), 2.00 (s, 6H, -CH3), 2.67 (b, 4H, -§H2-C5H11),
7.00 (s, 1H, methine proton).

4'-(2-Hydroxycarbonylethyl)-3,4-diethyl-3',5,5'-tri-

methyl—2,2'-dipyrromethenium bromide 24

3-(2-Methoxycarbonylethyl)-2,4-dimethylpyrrole 3b (1.87
g 0.11 mole) and 2-formyl-3,4-diethyl-5-methylpyrrole 22

(2.06 g 0.11 mole) were heated in 20 ml methanol on a steam

49
bath. 48% HBr (15 ml) was added in one portion to the hot
solution and heating was continued for 80 minutes until gas
evolution (carbon dioxide) ceased. 0n standing at room
temperature overnight, brown needle crystallized. The
product was collected by filtration, washed with ether and
air dried to give 4.23 g (95%). m.p. 183-184°C. p.m.r. 1.06
(t, J = 8.0 Hz, 3H, -CH2-£H3), 1.20 (t, J = 8.0 Hz, 3H,
-CH2-£fl3), 2.23 (s, 3H, -CH3), 2.63 (s, 6H, -CH3), 2.40-3.00

CH CO0H), 6.90 (s, 1H, methine proton), 12.8 (b,

(b,4H,-gh 2

2H, NH).

Porphyrin Synthesis from Dipyrromethenium bromide
2,2'-Dimethyldipyrromethenium bromide (1.0 mmol) and
2,2'-dibromodipyrromethenium bromide (1.0 mmol) were suspended

in formic acid (5.0 ml, 100%). The mixture was refluxed in

an oil bath (120°C), the 50.1 ul of bromine was added. The
solution was refluxed for 2.5-3 hrs. The solvent was then
allowed to boil off. The residue was dissolved in 20 ml
methanol and then 1 ml concd. sulfuric acid and 10 ml tri-
methyl orthoformate were added. After standing overnight,

30 ml dichloromethane and 100 ml water were added to the
mixture. The organic layer was washed, separated, and
evaporated to dryness. ,The crude product was purified by
chromatography on silica gel TLC plates, using dichloromethane:
methanol 95:5, as the devel0ping solvent. The porphyrin band
was collected and rinsed off with methanolzmethylene chloride
5:95. After removal of solvent, the solid was dissolved in
minimum amount of methylene chloride and diluted with

methanol to precipitate the crystals.

50
Methyl-1,2,3,4,5,8-hexaethyl-6-methyl-7-prgpionate
porphyrin 26a

 

m.p. 185-186°C. p.m.r. 1.85 (t, 0 = 7.5 Hz, 18H, -CH2-

CH ), 3.08 (t, J = 7.5 Hz, 2H, -CH2£fl2COOCH3), 3.40 (5, 3H,

3

-CH3), 3.50 (s, 3H, ~C00CH3), 3.93 (0. J = 7.5 Hz, 12H, -gH2-

CH3), 4.17 (t, J = 7.5 Hz, 2H, -§fl£CH2COOCH3), 9.73, 9.77,

9.83, 9.85 (s, 4H, meso), -3.77 (6, 2H, NH). VIS: 397, 496,

530, 565, 618 nm. N+ = 578. Anal. Calcd. for C H N 0 -

37 46 4 2'
C, 76.78; H, 8.01, Found: C, 77.04; H, 7.81.
Methyl-1,2,3,4-tetraethyl-6,7—dimethy]-5,8-dipropionate

pprphyrin 26b

 

m.p. 150-152°C. p.m.r. 1.87 (t, a = 7.5 Hz, 12H, -CH2CH3),
3.17 (t, J = 8.0 Hz, 4H, -CH2£H2COOCH3), 3.53 (s, 6H, -CH3),
3.57 (s, 6H, -0CH3), 4.03 (t, 0 = 8.0 Hz, 4H, -CH2CH2C00CH3),
4.27 (0, J = 7.5 Hz, 8H, -CH2CH3), 9.86 (b, 4H, meso protons),
-3.70 (b, 2H, NH). v15: 398, 496, 530, 566, 620 nm. M+ = 622;

Anal. Calcd. for C38H46N404: C, 73.28; H, 7.45, Found: C,

74.40; H, 7.46.
Methyl-1,2y3,4-tetraethyl-6,7-dimethyl-5,8-diacetate

porphyrin 26c

 

m.p. 295°C. p m.r. 1.83 (t, 0 = 7.5 Hz, 12H, -CH pH

2 3).

3.23 (s, 6H, -CH3), 3.60 (s, 6H, -OCH 3.93 (q, J = 7.5 Hz,

3).

8H, -CH CH 4.67 (s, 4H, ~Cfl2COOCH3), 9.40, 9.76 (s, 2H,

2 3),
meso H), 9.67 (s, 2H, meso H), -4.00 (b, 2H, NH). v15: 399,

+
497, 532, 566, 620 nm. M — 694 for C36H42N404.

Methyl-I,4,6,7-tetramethyl-2,3-dihexyl-5,8-dipropionate

 

porphyrin 26d

 

m.p. 183-185°C. p.m.r. 0.88 (t, J = 5.0 Hz, 6H,

-(CH2)5£H3), 1.10-1.90 (b, 12H, -(9H CH3), 2.00-2.50

2)3‘

51
(b, 4H, 'flzC4H9), 3.15 (t, J = 8.0 HZ, 4H, 'flz'COOCH3),
3.46, 3.53 (s, 6H, -CH3), 3.60 (s, 6H, -C00CH3), 3.92 (t,
0 = 7.0 Hz, 4H, -CH2C5H11), 4.26 (t, J = 8.0 Hz, 4H,
~§H2CH2C00CH3), 9.78 (b, 4H, meso H), -3.83 (b, 2H, NH).
v15: 402, 498, 531, 565, 622 nm. M+ = 706; Anal. Calcd.
for C44H58N404: c, 74.96; H, 8.01; Found: C, 74.69; H,
7.90.

Alternative synthesis of 26d by saturated HBr formicacid

 

292 mg of 19d and 213 mg of 16b was dissolved in 10 ml
HBr-saturated dry formic acid and refluxed at 140°C for 2.5
hr. After purification 30.3% of 26d was obtained.

Methyl-1,4,6,7-tetramethyl-2,3-dihexyl-5,8-diacetate

poLphyrin 26e

 

m.p. 240-2420C. p.m.r. 0.87 (poorly resolved triplet,
6H, -(CH2)5-§fl3), 1.20-2.00 (b, 12H, -(£fl2)3-CH3), 2.00-2.60
(b, 4H, -£fl2-C4H9), 3.40, 3.46, 3.63 (s, 6H, 6H, 6H, -CH3,
-0CH3), 3.90 (t, J = 8.0 Hz, -§H2-C5H11), 4.77 (s, 4H, 7952‘

COOCH3), 9.73, 9.80 (s 1H, 3H, meso H),-3.67 (b, 2H, NH).

VIS: 397, 496, 530, 565, 620 nm. M+l= 678; Anal. Calcd. for
C42H54N4O4. 1 1/2 H20: C, 71.48; H, 8.08, Found: C, 71.31;
H, 7.61.

Methyl-2,5,8-trimethyl-3,4-diethyl-1,6,7-tripropionate

 

porphyrin 26f

 

m.p. 148-150°C. p.m.r. 1.80 (t, 0 = 8.0 Hz, 6H, -CH2£H3),

3.10 (poorly resolved triplet, 6H, -CH2-£H2C00CH ), 3.40 (b,

3
9H, -CH3), 3.60 (s, 3H, -COOCH3), 3.86 (q, J = 8.0 Hz, 4H,

-£fl CH3), 4.10 (t, J = 8.0 Hz, 6H, -£fl -CH COOCH 9.70

2 2 2 3)’

52
(b, 4H, meso H), -3.60 (b, 2H, NH). VIS: 396, 496, 530, 564,
+
617 nm. M - 666; Anal. CaICd. for C39H46N404: C, 70.25;
H, 6.95, Found: C, 70.20; H, 6.86.

1,4-Bis(2-chloroethyl)-2,3,5,8-tetramethyl-6,7-bis(2-

 

methoxycarbonylethyl) porphyrin 26g

 

m.p. zoo-202°C. p.m.r. 3.17 (t, a = 7.0 Hz, 4H, 'EE -
COOCH3), 3.30 (s, 3H, -CH3), 3.32 (s, 3H, -CH3), 3.60 (s, 6H,
-0CH3), 3.80—4.50 (m, 12H, -QH2§H2C1, -CH2
(broad, 3H, meso proton), -4.07 (broad, 2H, NH). MS, field

662.

CHZCOOCH3), 9.57,

desorption, M+

2,3-Bis(2-chloroethyl)-1,4,6,7-tetramethyl-5,8-bis(2-

 

methoxycarbonylethyl)porphyrin 26h

 

m.p. 215-217°C. p.m.r. 3.07 (t, 0 = 7.0 Hz, 4H, -gH2-

COOCH3), 3.33 (s, 6H, -CH3), 3.33, 3.43, 3.50 (s, 18H, -CH3,

-0CH3), 3.90-4.40 (m, 12H, -gH CH C1, -gH COOCH3), 9.53,

2-—2 2 2
9.57, 9.63 (s, 1H, 1H, 2H, meso protons), -4.00 (broad, 2H,

CH

NH). v15: 416, 500, 528, 566, 619 nm. M+ = 662

Methyl-1,4,5,8-tetrapr0pionate 2,3,6,7-tetramethyl

 

porphyrin 26k

 

I. 425 mg of 5,5'-dimethyldipyrromethenium bromide 16b
was dissolved in 100 ml dry formic acid and heated to 100°C
in an oil bath (130°C) for 5 min. 0.15 ml bromine was added
and the mixture refluxed for another 2 hrs.' After isolation
and esterification, 2% of porphyrin 26k was obtained. m.p.

183-185°c. p.m.r. 3.20 (t, 0 = 8.0 Hz, ~99 -C00CH3), 3.60

2

(S, 24H, -CH -CH3), 4.30 (t, J = 8.0 Hz, 8H, -CH CH COOCH

3’ 2 2 3)’
7.81 (s, 4H, meso H), -3.66 (broad, 2H, NH). VIS: 400, 498,

533, 367, 622 nm M+ = 710.

53

II. 1 g of 3,3',5,5'-tetramethyl-4,4'-dimethoxycarbonyl-
ethyl dipyrromethene 16b was dissolved in 5 ml acetic acid
followed by 0.8 ml of bromine. The mixture was allowed to
stand overnight at room temperature. Crystals formed in the
mixture were filtrated and washed with hexane to give 0.92 g
of 25. 200 mg of 25 was dissolved in 10 ml formic acid
mixed with 1 ml conc. HCl. The mixture was refluxed at
140°C for 15 hrs. After purification, 10 mg of 26k was
obtained in 4% yield.

The dehydrochlorination of 2-chlor0ethyl porphyrins to

vinyl porphyrins. General procedure [20]:

Bis(2-chloroethyl)porphyrin 10 mg was dissolved in a
mixture of 4.5 ml pyridine and 10 ml 3% NaOH and the mixture
was refluxed for 1.5 hr. The solution was neutralized with
6H acetic acid before extracting with methylene Chloride.
The organic layer was separated and dried over sodium sulfate
and evaporated under reduced pressure. The residue was dis-
solved in a mixture of 10 ml methanol, 5 ml trimethyl ortho-
formate and 3 drops of concd. sulfuric acid, and *was
allowed to stand overnight. After removal of the solvent,
and dried under vacuum, the solid was recrystallized from
methylene chloride-methanol.

1,4—Divinyl-2,3,5,8-tetramethyl-6,7-bis(2-methoxy-

carbonylethyl) porphyrin 26i

 

Yield: 56%. m.p. 208-210°C. v15: 408, 506, 548, 576,
630 nm. M+ = 590.

54

2,3-Divinyl-1,4,6,7-tetramethyl-5,8-bis(2-methoxy:

 

carbonylethyl) porphyrin 26j

 

Yield: 60%. m.p. 260-262°C. v15: 402, 502, 536, 570,
625 nm. MS: field desorption, M+ = 590.

55

1114411

aNH :_L>;aeo¢ we Esguumam m2;

«I. o N v

1 J 4 ‘
.‘4N1NN114.-11411111111‘1141 ‘111‘4144111 4{1‘49‘119‘d‘l‘9‘j‘9‘991{1‘11 ‘

 

R

J

 

 

56

111111 #1111111111111111114111111111‘114111111‘1<1111114d1111111|11q11

oNH eweseecoe ea sseeoeem use .N-N .meu

111 1
1 1 111111 11 11111 111 111 11111 1 1111111 11 11 111

 

 

 

d 1 d 1 d 1 d 1 d 1 111411 11 d 1E 111.1 11111 E1
)7 It I h v
1111. 111.1 1:. _ i 4
.

 

 

 

 

 

 

 

57

ma cesxsaeoe 4o Escuumam as;

 

.mim

.3:

 

58

new eweseecee Le secpooem «2e

.eim

.m_u

o—

 

 

1111111‘11111

 

59

 

 

 

 

 

 

ems eecseecee ea asceooam «:8 .m-~ .321

EA:—
.°.m .

gig; 1%;‘Mféét mflazérwrzé:

 

 

 

 

 

 

 

 

60

e...

 

 

 

nNH cecasagom we Escuomqm xzu

Ema.

6....

331+

 

 

 

 

.952:

_

 

 

 

 

OO—

[P

 

1312132? ,

 

.e-~ .3“.

 

 

 

 

61

f0

mH cwexcaeoa mo Ezcuumam mzu

::_m
G

6.... o.

 

 

 

 

 

 

_ its...

 

 

 

 

 

 

CHAPTER 3
SYNTHESIS OF COFACIAL AND SLIPPED DIPORPHYRINS

Introduction

In the past few years, several types of diporphyrins
have been synthesized. These cofacial diporphyrins have great
significance in many branches of Chemistry. As organic
molecules, in addition to being challenging synthetic targets,
they can present a multitude of properties by the mere token
of their size and by the resulting interaction of the two l8
n-electron porphyrin ring. As inorganic compounds, they have
the unusual capability of containing two metal ions at
selected distance and thus can display interesting properties
arising from metal-metal interaction. Furthermore from the
point of view of biochemistry, they represent a class of
elaborately designed bioinorganic models for many essential
biological systems; among these were:

(1) "special pair" chlorophyll model in photosynthetic

unit.
(2) cytochrome oxidase model capable of multielectron
reduction of oxygen.

(3) polynuclear complexes with certain catalytic activity.

Collman and his coworkers [35] in 1977, synthesized a
face-to-face porphyrin by the dimerization of two functional-

ized mesa-tetraphenylporphyrin derivatives. We have also

62

63

reported, in the same year, a series of diporphyrins [27,36,
37]. These dimers were linked by two amide bonds at the
pyrro-B-positidns. The distance between the porphyrins can
be varied by changing the bond length. Ogoshi et al. [38]
also reported the preparation of a B-linkage diporphyrin.
However, the absorption spectra of their diporphyrin suggest
that the compound may not be a cofacial dimer. Wasielewski
et al. [39] prepared a chlor0phyll dimer as a model of
special pair chlorophyll. Kagen et al. [40] prepared a dimer
by linking para-substituted mesa-tetraphenylporphyrins.

Recently Collman [41,42] reported several diporphyrins
linked at either the meso positions, or at the pyrrole 8-
positions, using the same synthetic approach reported by us.
The interplanar distance was varied from 6.5 3 to 4 A. A
dramatic 4-electron electrocatalytic reduction of oxygen was
observed with one of the cobalt-cobalt diporphyrins [43].

In this chapter we describe the synthesis of several
cofacial diporphyrins as well as a "slipped" diporphyrins.
Unusual properties of the diporphyrins and the experiments
using diporphyrins as a photosynthetic reaction center model

are also discussed.

Results and Discussion

 

A. Synthesis of Diporphyrins

 

(1) Synthesis of dimers

 

With the large variety of difunctionalized porphyrins
described in Chapter 2, at least 2 types of cofacial di-

porphyrins can be synthesized. The first is a true face-to-face

64

dimer resulting from the coupling of two 1,5-difunctionalized
monomers (32 and 30 or 35). The other is a "slipped" dimer
obtained from the coupling of a 1,4- and a 1,5-disubstituted
porphyrins (36 and 30 or 35) (see Fig. 3-1).

The coupling of the diamine and diacid chloride was
affected with a high dilution, mixing procedure, using equ-
molar solutions concentration ca. 5 mM of the porphyrin di-
amine and diacid Chloride in dichloromethane. Triethylamine
was added to the solution of porphyrin diamine, in order to
increase the solubility and catalyze amide bond formation.
Work-up consists of removal of the solvent on a rotary
evaporator, dissolution of the residue in dichloromethane,
and passage through a short silica gel pad to remove the
polymer and unreacted amine. The dimer fraction was further
purified on preparative TLC plat.

The dimers prepared by this route may give two isomers,
designated as "syn" and "anti" (Fig. 3-2). Attempts to
separate them on TLC plates have been unsuccessful.

Metal ions such as Cu, Co, Mg were inserted in the dif
porphyrins by standard procedure [12]. Mixed dimetal system
were prepared by coupling the metal complex of an acid
chloride with the free base diamine, followed by subsequent
metal insertion. Using this approach, Cu-Fe and Mg-H2 di-
porphyrins have been successfully prepared. Upon chroma-
tographing on silica gel plate, the Mg-Mg dimer also de-
metalizes to give a Mg-H2 dimer. The physical properties of

these dimers were listed on Table 3-1.

65

 

SLIPPED A COFACIAL

Fig. 3-1. Cofacial and Slipped Diporphyrin

    

R=n'hexyl
SYN- R'=n-butyl

_.ANn-

Fig. 3-2. Syn and Anti Configuration of Diporphyrins

66

(2) Preparation of secondary porphyrin diamines

The diester porphyrins 27 are reduced by lithium
aluminium hydride in THF to the diols 28 which, in turn, are
converted to their mesylates 29 by treating with methane-
sylfonyl chloride in dichloromethane/triethylamine. Re-
fluxing with n-butylamine gave the diamine 30 in almost
quantitative yield from 27.

(3) Preparation of primary porphyrin diamines

The diester porphyrin 27 was hydrolyzed to diacid
dihydrochloride 31 and these could be converted to the di-
acid chloride 32 with oxalyl chloride. The diacid 31d was
insoluble in methylene chloride and oxalyl chloride. The
presence of a small amount of phosphorus oxychloride was
necessary to achieve the conversion. Treatment of the acid
chloride in methylene chloride with sodium azide in water
using tetrabutylammonium bromide as phase transfer catalyst,
gave diacid azide 33. Upon heating in dry benzene, these
were converted to the diisocyanate derivatives 34 without
further purification. IR was used to monitor the progress of
the rearrangement, which was complete in 4 hrs.

The diisocyanate was used without isolation to give the
primary diamine porphyrin 35 by acid hydrolysis. The diamine
was purified by passing through a silica gel pad, using a
methylene chloride:methanol:triethylamine 100:10:0.5 solvent
mixture as elutent. The diamine can be stored in freezer for

months without decomposition.

27a

(DO-OCT

28a

67

 

R1=C8
R1=C6
R1=C6
R1=C5
R1=C5

R1=C8
R1=C6
R1=C6

R1=C8
R1=C6
R1=C6

R1=C8
R1=C6
R1=C6

R2=COOCH

3
R2=CH COOCH

2 3
R2=C00CH3
R2=CH2C00CH3
R2=COOCH3
R2=CH20H
R2=CH2CH20H
R2=CH20H

R2=CH20Ms
R2=CH2CH20MS

R2=CH2NBu
R2=CH2CH2NBU

R2=CH2NBU

33a

34a

35a

R1=C6
R1=C6
R1=C5
R1=C5

R1=C6
R1=C6
R1=C5
R1=C5

R1=C5

R1=C5

R1=C5
R1=C5

R1=C5
R1=C5

R2=CH2COOH

R2=COOH
R2=CH2C00H
R2=COOH

R2=CH2COC1
R2=COC1
R2=CH2C0C1

R2=COC1

R2=CON3

R2=NCO

R2=CH NCO

2

R2=NH2
R2=CH2NHZ

68

 

36a R1=C6 R2=CH2CH2COC1
b R1=C6 R2=CH2COC1

c R1=C5 R2=CH2COC1

47COCI g

cocu . .

gCOCI I:

COCI
SLIPPED

69
B. Nuclear Magnetic Resonance Spectrosc0py

NMR spectroscopy is a particularly useful technique for
establishing the integrity of a porphyrin dimer. If one
porphyrin ring is positioned atop another, the ring current
of the second porphyrin can cause additional shifts of the
proton resonance, in particular, the NH signals [35].

The diporphyrins prepared by this route consists of two
isomers. The meso protons have a chemical shift in the
region at 8 ~10 ppm. More than 4 peaks were observed in this
region indicating a mixture of the syn and anti isomers
(Fig. 3-3). In a similar dimer reported by Collman [41]
obtained from a different approach only 4 peaks were found.

The nitrogen protons of the monomeric porphyrin were
observed at -4 ppm, while those of dimers were shifted to
higher field by the ring current interaction. The shift of
NH protons seem to reflect the distance between the two
porphyrins; the closer the dimer, the larger the shift. The
slipped dimer 505 has a smaller shift than the face-to-face
F05 dimers. The tertiary amide linked dimers FD6(NBu), F05
(NBu) were shifted further than the secondary amide linked
dimers FD6(NH), F05(NH). This may indicate that the secondary
amide linked dimers are more flexible than the tertiary amide
linked dimers. Indeed, the x-ray structure of Cu-Cu dimer
F07 has been shown to have a slipped structure [44].

Nmr signals of all peripheral alkyl substituents in the
region of 4.5-0.5 ppm could not be resolved because of the

isomeric nature and flexibility of the dimers. The sharper

70

ene e_cs;aeeeeo Le asepoeem eze .m-m .meu

o N v . . . o a o —

'r’b”"-ED’Pp’hpEFp”’.>rh’UPPR’b’Dt.’P”’»R”h’_i»pybp*"ht’b’””>b-”*rb’PR.b??>”>>>Php>’>é”’R’R’P

_

: J

 

71

ma

om

om
mm

.mcwsm_a;umwu

new mnwco_;u uwum uwpmuewu mo m:w_a:ou men an umcwmuno mm; AN+NVmou .mcwsm
-Fzgpmspu can mcweopsu u_ue uvcowaoeawu mo mcwpasou men an omengmea we: AH+mvmom

owe
omm
mum

owe
mmo
owe

Nmo
mum

mum
own

mmo

ewe
ewe

H

mmm
mom
oxm
mom
mom
mom
Nmm
0mm
0mm
mom
mmm
mmm
Nwm
0mm
cum
mom
cum
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com
Cum

Cum
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HH

omm
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umm
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cam
mvm
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mmm
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omm
mmm

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memewo mo meme mguumam m_> new as;

mom

com

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cam
¢Om

oam
mom

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mom
Nam

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omm
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momuuom+nmm

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oomunmm+u~m
oomnnom+mmm
“remunom+com
meomunom+mmm

mmzHo

72
signal of dimer F04 at room temperature is a evidence for its
more rigid structure.

C. Electronic Spectroscopy

 

The visible spectra of the dimers provided convincing
evidence of their conformations. All dimers showed a
distinct blue shift (10-27 nm) of the intense Soret band and
a weak red shift of the longer wavelength absorption [36,45].
The bands also appeared to be broadened. This strongly
suggests the presence of exciton interaction. The shifts of
the secondary amide linked dimers and tertiary amide linked
dimers differed by about 10 nm; this may be due to the extent
of slippage in the diporphyrins as the Soret band of the
slipped dimer was less shifted than the corresponding face-
to-face dimers. The shift of the Soret band and their
quenched fluorescence were useful in characterization and
identification of the diporphyrins during their preparations.
It is evident from comparisons of the visible spectra of

-Mg-H F05, Mg-Hz F04 versus the mixture of HZOEP and MgOEP

2
that there are significant interactions of the porphyrin
rings (Fig. 3-4).
0. Electron Spin Resonance Spectroscopy

The interplanar distances of the diporphyrins were
determined by studying the dipolar interaction of two para-
magnetic metal centers. Simple Cu(II) porphyrins have S=1/2
system with well-defined ESR characteristics [46]. If two

copper porphyrins are close enough such that the spins inter-

act, then the bimetallic system exhibit a triplet ESR spectrum.

73

 

 

..l

 

 

 

 

rice—U .N. T—OEV 010- X W

700

 

WAVE LENGTH (nm)

’
5
D
F

2
H

-
gP
ME
0
3.19
OM
/
aP
“IE
to
C
ed
0."
sa
S4
.10
VF
2
H
.-
49
.M
3
g
.1
F

74

If the rate of electron exchange between these two metals
is faster than the resonance frequency (1010/sec), then the
electron electron nuclear spin will equal to the total nuclear
spin of the two metals (I=3 for Cu(II)). Thus the Cu-Cu dimer
will exhibit 7 lines from the hyperfine interaction. At the
same time the hyperfine splitting A is half that for a related
monomer. The ESR transitions will be further split by the
zero-field splitting [ZFS],D. D is half the distance between
the centers of the parallel absorptions. A center is located
as the midpoint of seven hyperfine lines (see Fig. 3-5).

4

The ZFS splitting parameter 0 (10' cm) has been used to

estimate metal-metal spacing on the basis of eq.

D=0.65 gzz/r3.

2_ 2 2 2 . 2
92 —g11 Cos e + 92 S1n 6

where r (g) is the distance between the metal centers, is the
angle between 911 axis and the Cu-Cu direction and Z is the
interplane distance.

Several examples of ESR of di-copper porphyrins have
appeared in the literature [36,37,41,42].

For dimer F04, from the apparent zero-field splitting,
the Cu-Cu distance 3.8 R was obtained. The ESR spectrum of
Cu-Cu slipped dimer 505, showed weaker metal-metal inter-

action.

75

we; :uizu mo

 

 

Ezsuuogm mmm

.mim

.mI

 

 

 

76
E. Cyclic Voltammetry

 

From the cyclic voltammetry measurements, the redox
potential of the metal and the effect of the metal-metal
interaction can be obtained.

The Co(II)-C0(III) couple of C0-C0 dimers were shifted
to more positive potential than that in their monomer. For
dimer F04, the voltammetric wave was split into two waves
(i.e. the second electron transfer is more difficult than
the first). This is due to the interaction of two metals
[41].

With the slipped dimer 305, there is only one wave at
0.61 V, indicating a weak interaction between two cobalt

metals (Table 3-2).

Table 3-2. Redox Potential of Cobalt
porphyrins from C.V.

 

Rin
Co(II)%Co(I) Co(II)$C0(III) Reduction Oxidation
COOEP -1.05 0.30 -1.87 1.26, 1.06

CofaciaI -1.00,-1.20 0.55, 0.81 ---- 1.23, 1.05

DM-4,
Co-Co

Slipped -o.97 0.61 ---- 1.25, 0.93

DM-S,
Co-Co

 

F. Oxygen Interaction with Dicobalt Porphyrins

 

When a bulky ligand, 1-tritylimidazole, was complexed
with Co(III)-Co(II) diporphyrin-7 and exposed to oxygen, the

visible, ESR spectra, and gasometric data all documented the

77
formation of a double 1:1 Co-02 compound. The oxygen
affinity of this system was similar to those of monomeric
Co(II) porphyrins. Complete oxygenation at 1 atm of 02
could be achieved below -300 and the oxygen binding was
completely reversible [36]. Co(II)-Co(II) diporphyrin-5,
on the other hand, reacted quite differently with oxygen.
Addition of02 to the [03 CIm-Co(II)] complex at room
- temperature instantaneously produced a species consistant
with the formulation of 2Co/02 (gasometry Co:02=1:0.55).
This complex represented as [Co(III)-02-Co(III)], was dia-
magnetic and had no ESR signals. This u—peroxo complex,
however, can be oxidized readily to show a well-defined iso-
tropic ESR spectrum consisting of 15 lines (Fig. 3-6A, g.

1so=
CO|=10 Gauss). This is interpreted as a u-superoxo

2.024, |A
[Co(III)-0-Co(III)] complex in which the two equivalent Co-
59 nuclei (I=7/2) would give a total of (2x2x7/2)+1=15 lines.
This assignment has been substantiated by 0-17 experiments
[37].

Behavior of the Co(II)-Co(II) diporphyrin-4 was similar
to the dimer-5, i.e. a u-superoxo complex formed readily
using the iodine oxidation method. A careful comparison of
the 15-lines, u-superoxo ESR spectra (Fig. 3-6B), however,
indicates that the hyperfine lines of the dimer-4 have
narrower line-width and Consequently, the splittings are
more symmetrical and better resolved, in comparison with the

dimer-5. We believe that the spectral difference, albeit

small, is indicative of the variation of the cobalt-oxygen

78
bonding in the diporphyrins. Recalling the extent of
slippage of the diporphyrin structure, we suggest that the
superoxo bridging Iigand is bound in a trans-configuration

in diporphyrin-5 but in a Cis-geometry in diporphyrin-4.

 

There are two lines of evidence which seem to sub-
stantiate this proposal. First, many welleknown cis-u-
superoxo binuclear cobalt complexes having an amido bridge,
such as A, invariably exhibit symmetrical, sharply resolved
hyperfine lines [47,48], very similar to the spectrum of
diporphyrin-4. 0n the other hand, trans-p-superoxo cobalt
complexes, such as 8, generally have a more diffused
spectrum with larger line width for the hyperfine components.
The difference has been attributed to the orientation of the
lone-pair electrons on the oxygen yielding a local electric

field perpendicular to the Co-Co axis [49].

79

Co-Co-5
A
|
2024
Co—Co-4
B .
“' ‘ WWW\.MMM
I
20197

Shpped Co-Co-4

WNW”

2025

ICC Gauss

Fig. 3-6. ESR Spectra of u-Superoxo Co-Co Diporphyrins

A. Diporphyrin-5 B. Diporphyrin-4
C. Slipped Diporphyrin-4

80

0-0 '
/ \ L Co-O
L4‘5° \"Hz/ “'11 5 \0- CoL5
A E

The slipped dimer-4 provided a further test of this
proposal. In this molecule, the two rings are slipped by
about 2.5 A and the bridging oxygen ligand must bind in a
trans-configuration. As shown by Fig. 3-6C, the u-superoxo
complex indeed exhibited the poorest resolved line shape.

Recently, binculear Co(II) and Fe(II) diporphyrins
have been applied to the surface of graphite electrodes and
tested for catalytic activity toward the electron reduction
of dioxygen to water in aqueous electrolytes [42]. Most
dimers tested exhibited some catalytic activity, but usually
hydrogen peroxide rather than water was the major reaction
product. However, Collman, Anson, and associates have re-
ported [42] that a Co(II) Co(II) dimer FD4, similar to the
one discussed above has produced a catalyzed reduction
almost exclusively to water. Rotating ring-disk voltammetry
was employed to diagnose the electrode reaction. It is un-
clear as why only the dimer-4, not the dimer-5, would give L

the activity since both dimers are capable of intercalating

81

molecular oxygen. Perhaps the cis-configuration of the
diporphyrin-4, being more exposed to solvent, is more
accessible to proton transfer and thus facilitates the
cleavage of the stable peroxo bond. Similar consideration
may be relevant to cytochrome oxidase activity since main-
taining a flux of proton supply is as important as sustaining
an electron flow at the oxygen reduction site.
G. Steric Effect in Oxygen and Carbon Monoxide Binding

X-ray structures of CO-hemoglobin and CO-myoglobin
exhibit a bent or tilted configuration of the C0 ligand with
respect to the porphyrin ring [50], whereas in heme model
compounds, the Fe-C—O bond is linear and perpendicular to
the heme plane [51]. The origin of the different configura-
tion is attributed primarily to nonbonding steric interactions
of the axial ligand with residue at the distal side. This
steric effect was postulated to decrease the affinity of CO
(in heme proteins [52]. An assumption is generally made that
ligands such as 02 and N0, which preferentially form bent
complexes, should not suffer this steric effect [36,37].
Therefore, equilibrium and dynamic studies of 02 and C0
binding to the tightly spaced Fe-Cu diporphyrin should provide
an excellent model to evaluate the steric effect on heme-
ligand coordination.

The Fe-Cu dimer-4 was chosen for study because of its
very short and rigid structure which could impose steric
strain to the axial ligand(Fig. 3-7). Equilibrium constants

of C0 and 02 binding to the ferrous heme were determined in

82

 

Fig. 3-7. Carbon Monoxide Binding to the Sterically
Crowded Fe-Co Diporphyrin-4

83
benzene solution containing 0.2 M of N-methylimidazole. The
nitrogen base can only coordinate only at the outside of the
dimer to give a 5-coordinate heme. Kinetic rates were deter-
mined by a flash photolysis method [52] which permits direct
measurements of C0 and 02 association rates as well as the
the 02 dissociation rate. The C0 dissociation rate was
calculated by Lco = '1lififir . The rate constants are
tabulated in Table 3-3.

A comparison of the kinetic and equilibrium data of the
Fe-Cu-dimer and those of a 5-coordinate mesoheme in nonpolar
solvents clearly indicates that the effects of steric
hindrance are mainly manifested in the ligand association rate
constants. The C0 association rate seems to be reduced more
than the 02 rate and the result is that both 02 and C0
affinities are reduced but not to the same extent. This can
be seen by the smaller M value of the dimer. These findings
are in good agreement with the prediction made earlier by
Moffat et al. [50] on what effects steric hindrance have
upon ligand binding to heme proteins. It should be mentioned,
however, that solvent effects can also play a major role in
controlling equilibrium constants in small model compounds
[52,55]. It is not clear from our data whether the
relatively small variation in C0 and 02 off rates is due to
steric effects or to local polarity effects. Further work
is in progress to clarify this point. An important point
contained in the Table 3-3 is that if steric effects only

affect the ligand on rates then such effects are insignificant

in R-state hemoglobins. Indeed, Traylor and coworkers [52,56]

84

m<eu NN e? eoeeoemsm .

 

 

 

mm oe em ONN eoN x e.N N.o N.o eoH x m ON: a: eeaem-N
mNo.oe N
Nm oeaON Hem.o omeofi NON x Nee .eNo.o eo.oeNo.o moH x mam o I eeeopmesz
mm omN m.o NN NON x o.m «Noo.o mNo.o eoN x e ON: Ime eeeaeeae .e:
mm cam o.N Ne NON x e.N NNoo.o moo.o eoN x e.m sON: oeeeeeoce eoea_oeu
. . . . eNoz-z
ooe oe OON moN x N m me o eNo o eofi x e N oeoNeee e-coeee su-ou
mm
Nm mes x N N.m CONN NON x m.m eooo.o mo.oa 60H x N peas—op asaeemae eoea_oeu
63m 2 .23 Tuwm Tumm T: .23 Piuwm F..umm 72 peg—om cczoaeou
N we we _ _
D so .
AueNN-oNv No eea o8 Le mewee_m pee tea meeapmeeu e=_eee_esem nee owpoeex .m-m e_eae

85

have shown the chelated protoheme model to bind both 02 and
C0 in aqueous suspension with binding rates and thermo-
dynamics almost identical to those of isolated hemoglobin
chains. For the same reason, on the other hand, the steric
effects may be very important in myoglobin and T—state Hb.
It seems clear that one should keep in mind that there are
many molecular processes that regulate the ligand affinity
in hemoglobin [50]; different effects contribute differently
at different stages of hemoglobin reactions for different
ligands. This is an ideal case in which model studies could
single out each molecular process, estimate the range and
magnitude of individual effect and hopefully, inspire the
direction for future elaborations.

H. Picosecond Measurement of the Electron Transfer in

 

 

Slipped Mg-H2 Dimer-$05

In our previous work with Netzel et al. it has been
shown that the cofacial Mg-Hzrdimer-S yielded the charge
transfer species with lifetime 380:40 ps in CH2C12 and
620:20 ps in CH2C12 with 0.1 M tetraethylammonium chloride
following a 530 nm photoexcitation. In order to examine the
effects of geometry, a slipped dimer-5 was synthesized. One
of the macrocyclies is displaced slightly from the other
resulting in a slipped diporphyrin and abbreviated as Mg-H2
(55) i.e. Mg and free base diporphyrin with two 5-atom
bridges.

Fig. 3-8 shows the excited state spectra of Mg-H2 (SS)

in CH2C12. The spectrum at t=13 ps is similar to that of

0.6

ABSORBANCE CHANGE
o .0
N b

.0
o

-O.2

86

 

 

 

 

 

 

 

Mg-H2(58) IN CH CI2(e=8.9)
H \
_. f3 \ _
\
\
\ _
\ \
\
//I\. \ \ _
/ \. \\
‘ \\
I. \( _.
f i\. \N
' e 1. .\\\ _
\-;::€::W‘i9§
[3 ps
----- 300ps
——600 ps _
—-—2ns
1 1 —i°—5”s 1
550 600 650 700 750

WAVELENGTH (nm)

Fig. 3-8. Excited State Spectra of Slipped Dimer-5

BOO

87
Mg-H2 (5) in CH2C12. The transient spectrum of 13 ps changes

to the spectrum which is similar to that at 300 ps with
estimated lifetime of 40 ps. The intensity longer than 680 nm
decreases. This suggests the disappearance of the CT product.
The spectrum at 300 ps looks like that of the singlet excited
state. The transient between 100 ps to 300 ps Changes little.
Then the spectrum after 300 ps decays with a lifetime of about
2 ns (not single exponential). The pmr spectrum of slipped
dimer-5 shows very complicated features which suggest multiple
configurations of Mg-H2 (SS) is considered to be dynamic
instead of static. Probably the majority of the molecules
have an open clam configuration which does not yield a CT
species. Only a small number of molecules which have an
overlap configuration yield CT product when excited. The
overlap configuration also changes by thermal motion resulting
in the ring opening or sliding. Based on the results of the
cofacial dimer Mg-H2 (5) and slipped dimer Mg-H2 (55), we can
conclude that in order to stabilize charge transfer species
the two porphyrin ring (donor and acceptor) are required to

have parallel configuration.

Experimental

 

Most of the experiment materials and instruments were the
same as described in Chapter 2.

Electron Spin Resonance Spectra

 

Spectra were collected on a Varian E-4 X-band spectro-
meter in a frozen glass (770K) of toluene and methylene

Chloride. The microwave frequency was measured by a cavity

88
wavemeter calibrated against the signal of diphenylpicryl-
hydrazyl (DPPH) (g:2.0036).

Cyclic Voltammetry

 

Reagent: methylene chloride was distilled over CaHz.
Polarographic grade tetra-n-butylammonium perchlorate (TBAP)
recrystallized three times from ethyl acetate/hexane before
use as supporting electrolyte.

Apparatus: Cyclic voltammetry were carried out with a
Model CV-lA instrument (Bioanalytical system Inc.). Current-
voltage curves were recorded on an Moseley model 700 AM X-Y
recorder. The reference electrode was an aqueous saturated
calomel electrode (SCE). The working and counter electrodes
were platinum.

Preparation of porppyrin amines

 

Reduction of diester porphyrin to diol 28

 

The diester porphyrin 27 (500 mg) was dissolved in 150
ml of THF. A suspension of LiA1H4(lg) in 100 ml dry THF was
added dropwise to the porphyrin solution with stirring. The
reaction mixture was checked by TLC, until all ester was
reduced to alcohol. The reaction was terminated by adding 1
ml ethyl acetate. The reaction mixture was passed through a
silica gel pad, which was then elueted with 5% methanol/methy-
lene chloride to give 28 in a 90% yield.

Mepylate porphyrin 29

 

The appropriate dial (400 mg) was dissolved in 1 ml tri-
ethylamine and 50 ml dry methylene chloride. The solution

was cooled in an ice bath with stirring. Methanesulfonyl

89
Chloride (0.5 ml) was added drop by drop and the reaction
was monitored by TLC. After all diol was converted to mesy-
late, the solvent was removed, and the residue dried in [3313:
The mesylate was used without further purification.

N-Butyl amine porphyrins 30

 

The mesylate (300 mg) was dissolved in pure n-butylamine
and refluxed overnight. After being checked by TLC to
indicate the completion of conversion, the excess butylamine
was removed on a rotary evaporator. The amine was precipitated
by adding water and the solid (90%) was collected by filtra-
tion and washed thoroughly with water. '

Prepgration of primary amine popppyrin

 

Diacid pogpyrin 31d

 

The methyl ester porphyrin 27e (500 mg) was dissolved in
30 ml 88% formic acid and 2 ml concentrated HCl, heated on an
oil bath and refluxed for 1 hr. The solution was cooled and
solvent was removed under reduced pressure. The residue was
dried under vacuum to give the diacid porphyrin dihydro-
chloride 535 mg (100%). The other diacids were prepared in
the same way.

Diacid chloride porphyrin 32d

 

Diacid 31d (535 mg) was dissolved in 2 ml P0C13, after
all solids were dissolved, 20 ml dry CH2C12 and 3 ml oxalyl
chloride were added. The solution was refluxed for 1.5 hr,
protected from moiture by CaClZ. The solvent and unreacted
oxalyl chloride were removed under reduced pressure and the

residue dried under vacuum for 1 hr, a dark red solid 563 mg

90
(100%) was obtained. The other acid chloride was obtained by
the same method without adding P0C13.

Diacid azide porphyrin 33a

 

The acid chloride porphyrin 32d (300 mg) was dissolved
in 25 ml dry methylene chloride. The mixture was cooled in
ice bath and a solution of sodium azide (1 g) and tetra-n-
butylammonium chloride (300 mg) in 10 ml water was added with
vigorous stirring. After 10 min, the methylene chloride was
removed under reduced pressure and a black solid was formed
in water solution. The solid was collected, washed with water
and dried under vacuum. The crude product was dissolved in
10 ml dry methylene chloride and passed through a silica gel
pad. The pad was washed with more methylene chloride (100 ml)
and the methylene chloride solution was concentrated under
reduced pressure to give di(acid azide) 33a (250 mg, 91%).
IR: 1710; 2135 cm‘l.
PMR: 0.93 (poorly resolved triplet, 6H, -(CH2)4QH3),
1.30-1.80 (broad, 8H, -(CH2)2-(§H2)2-CH3), 1.80-2.40 (broad,
4H, -CH2-gfl2-C3H7), 3.37 (s, 6H, -CH3), 3.43 (s, 6H, -CH3),
3.86 (t, J = 7.0 Hz, 4H, ~9fle-C4H9), 4.47 (s, 4H, -£H2-C00CH3),
9.67 (broad singlet, 4H, meso protons), -4.13 (broad, 2H, -NH).

Qipropionyl azide 33b was obtained in 98%
1

 

IR: 1690, 2140 cm-

Dimethylisogyanate porphyrin 34a

 

Di(acid azide) porphyrin 348 (250 mg) was heated under
reflux in dry benzene (100 ml) for 1 hr. The solution was

removed under reduced pressure, the residue was dissolved in

91
methylene chloride and passed through a silica gel pad. The
pad was washed with methylene chloride until no more product
was obtained, the solution was concentrated on an evaporator,
diisocyanate porphyrin 34a (207 mg, 90%) was obtained.
IR: 2250 cm‘l.

Diethyjisocyanate porphyrin 34b
1

 

IR: 2260 cm'

PMR: 1.00 (broad, 6H, -(CH2)4-gp3), 1.60 (broad, 8H,
'CHz-CH2'(c—H_2)2-CH3), 2.10 (broad, 4H, -CHz-£fl2-CBH7), 3060
-CH

-NCO, -§fl_-C H ),

2 2 2 4 9
9.83 (s, 2H, meso protons), 10.0 (s, 2H, meso protons).

(s, 6H, -CH3), 3.63 (broad, 12H, -£H

Dimethylamine porphyrin 35a

 

Diisocyanate porphyrin 34a (200 mg) was refluxed in 300
ml benzene and 200 ml_6N HCl for 1 hr. The mixture was
cooled and the benzene layer was discarded. 500 ml of 9:1:0.5
chloroformzmethanol:triethylamine was added into the acid
solution and this mixture was cooled in an ice bath. 50%
NaOH was added to the acid solution until it was neutralized.
The organic layer was washed with water and passed through
a silica gel pad. The solution was concentrated on an
evaporator, 145 mg of 35a was obtained (79%); no further
purification was necessary.

Diethylamine popphyrin 35b

 

This compound was prepared from 34b following the same

procedure as 35a in 70% yield.

IR: 1600, 3350 cm‘l.

PMR: 1.00 (broad, 6H, -CH2)4-QH 1.67 (broad, 8H,

3).

92

-(QHZ)2-CH3), 2.25 (broad, 4H, -Cfl2-C3H ), 3.63 (s, 6H, -CH3),
3.70 (s, 6H, -CH3), 4.00 (broad, 12H, -£H2-C4H9, -£H2-CH2-NH2),
4.70 (broad, 4H, -NH2).

General procedure for the diamide-linked diporphyrin

preparation

Bis(acid chloride) porphyrin was dissolved in 60 ml dry
methylene chloride and transfered to a 100 ml syringe under
nitrogen gas. Diamino porphyrin was dissolved in 1 ml dry
triethylamine and diluted with 60 ml dry methylene chloride,
the solution was transfered to a 100 ml syringe under nitrogen
gas. These two syringes were mounted on a motor-diver syringe
pump (Sage Instruments Co. Model 352). The solution in
syringes were injected at the same rate through stainless
needles into 500 ml dry methylene Chloride in a three-neck
1000 ml flask equipped with rubber septa and drying tube.
When the addition was complete (1 hr), the solution was
stirred for another hour. The mixture was evaporated under
reduced pressure, the residue was dissolved in 50 ml
methylene chloride and passed through a silica gel pad. The
pad was washed with methylene chloride until no more product
were eluted. The solution was concentrated to 5 ml, and
charged on preparative TLC plates. A solvent mixture (CHZClZ:
Me0H, 95:5) was used as the developing solvent to isolate
the diporphyrins. The diporphyrins prepared by this route
may give two isomers "syn" and "anti". Attempts to separate
them on TLC plate was unsuccessful. The diporphyrin bands

were collected from the TLC plates and extracted by 5% MeOH

93
in CHZClz. The solution was reduced to 1 ml and diluted with
methanol until precipitate formed. The solid was collected
by filtration. The visible spectrum and PMR chemical shifts
were listed on Table 3-1.
General method for copper insertion into porphyrins and

diporphyrins

 

Porphyrins and diporphyrins were dissolved in dry
methylene Chloride (20 ml) and treated with excess copper
acetate monohydrate dissolved in methanol. The mixture was
refluxed for about 10 min. After the reaction was completed
(monitor by visible spectra), the solution was concentrated
to 1710 volume and the precipitate was collected by filtra-
tion and washed with methanol.

General method for the preparation of MggMg and Mg-H2

diporphyrin

 

60 mg of magnesium metal and 1 ml iodomethane were
added to 10 ml dry ether and refluxed until all metal was
dissolved (about 30 min). 100 mg of 2,6-di-t-butylphenol
was added to the Grignard solution, a yellowish solution was
obtained. Diporphyrin was dissolved in 50 ml dry methylene
chloride and the magnesium reagent was added. After swirling,
a cherry-color solution was obtained. The solvent was
reduced under reduced pressure to 1 ml, 20 ml methanol was
added and the precipitate was collected by filtration. The
Mg-Mg diporphyrin was obtained quantatively. The Mg-Mg
diporphyrin was dissolved in 2 ml methylene chloride and

charged on a TLC plate. After development by methylene

94

chloride, two pink color bands were obtained. The first band
is Mg-Mg diporphyrin and the second band is Mg-H2 diporphyrin.
The products were collected by washing the silica gel bands
with methylene chloride.

Cu-Fe dimer 4 [42]

1. Copper was introduced into the diacid porphyrin 310
by the copper acetate method and visible spectra confirmed
the absence of free base porphyrin. The copper porphyrin
(150 mg) was dissolved in 100 ml dry pyridine and 300 mg of
p-nitrophenyl trifluoroacetate was added. The mixture was
stirred overnight at room temperature under dark. The nitro-
phenyl ester gradually separated as brick-red microcrystals;
100 ml hexane was added and the mixture was cooled in an ice
bath. The product was collected by filtration and washed
with hexane to give 140 mg (73%) of nitrophenyl ester. The
copper nitrophenyl ester porphyrin (140 mg) was dissolved in
100 m1 dry pyridine, 90 mg of diamino porphyrin 35a in 30 ml
warm dry pyridine was added, and the mixture was stirred at
70°C for 7 hr, light being excluded. The reaction was
monitored by TLC to ascertain that all phenyl ester reacted.
The solution was concentrated on an evaporator and dried under
vacuum. The residue was dissolved in methylene chloride and
washed with 10 ml 10% NaOH solution, then water. The organic
layer was passed through a silica gel pad to remove the
polymers and unreacted diamine. The dimer fraction was con-
centrated to 1 ml and diluted with methanol to form crystalline.

Cu-H2 dimer-4; 50 mg was obtained (yield 27%). Iron was

95

inserted into the Cu-H2 dimer using the ferrous sulfate method.

Cu-Fe Dimer-4 and Dimer-5

II. Copper was introduced into the diacid porphyrins 3lc
and 31d by the acetate method. The acids were converted to
acid chloride by reaction with oxalyl chloride. The respective
acid chloride was coupled with amine 35a to obtain the Cu-H2
dimer-5 and 4. Cu-Fe dimers were obtained by inserting iron

to the Cu-H2 dimer. No further purification was necessary.

CHAPTER 4

SYNTHESIS OF PORPHYRIN- AND CHLORIN-
QUINONE DONOR-ACCEPTOR PAIR

Introduction

 

In photosynthesis, the functional unit is composed of
several hundred chlorophyll (chl) moelcules in a protein
matrix, a special pair of chl molecules which is the site of
primary photoact, and a series of primary and secondary
electron donors and acceptors. The primary photochemical
process in algal and green-plant photosynthesis is known to
be an one-electron transfer reaction from a chlorophyll donor
to a plastoquinone acceptor. A similar process takes place
in bacterial photosynthesis where the acceptor is a ubiquinone.
The positive change left on the Chlorophyll donor is ultimately
linked to the oxidation of water.

One way to learn the primary events in photosynthesis
is to synthesize a model system that would mimic some of the
properties of photosynthetic apparatus.

In order to mimic the electron transferred process
there are several approaches to be taken. One is to work
with artificial membrane or micelles. Using detergents, one
can prepare micelles, or artificial membranes absorbed with
these chlorophyll orartificialpigment molecules. Electron
donors and acceptors can be added to each side of the membrane.

Upon illumination of this system, if proper components are

96

97

present, one can observe light promoted oxidation-reduction
reactions.

The bilayer lipid membrane (BLM) has been widely used
as a light active model membrane since the photoelectric
effects of BLMs were discovered in 1968 [58]. Several
quinone-porphyrin compounds have been synthesized as the
electron-transfer carrier. Tabushi et al. [59] have attached
a benzoquinone to a TPP. Loach and King [60] have synthesized
a similar compound with different chain length between
quinone and TPP. Sanders [61] reported a quinone capped
metalloporphyrins. On the other hand, because of the in-
stability of Chlorins, there was no chlorin-quinone compound
reported. Chang [62] has recently synthesized a stable methy-
lated chlorin from OEP; it should be possible to link a
quinone to this chlorin to form a quinone-chlorin compIex.
In this study several quinone-porphyrin compounds were also

prepared from the mono-propionate porphyrin 13.

Results and Discussion

 

The monoketone chlorin was converted to ethyl acetate
by lithio ethylacetate and then reduced by HI [63]. The
monoester of porphyrin 13 and chlorin 37 were converted to
butylamine 38 and 39 following the same procedure as Chapter
2. The synthesis of the quinone-porphyrin and -Chlorin were
shown in Scheme 4-1,2.

In order to overcome the instability of the hydroquinone
during the linking process, the hydroxy groups was blocked

by converting them into the acetate 40. The acid group was

98

Scheme 4-1.

 

CHz—CHz-CHz—N—C—R
C4H9
0A: 0C313
43 R = O 46 R =
"CH2
0: otflia
OH OH
44 R == ii.“ 47 R = _<}‘ [:3]
OH OH
0
0
45 R = [I'D all]
0 48 R = 'CH2
0

99

Scheme 4-2.

 

100
activated with thionyl chloride to get the acid ChJoride 41
and 42 and then condensed with the amines 38 and 39. In
order to obtain the hydroquinoneyl functionality, 43 and 49
were hydrolyzed by methanolic hydrochloric acid. Compound
46 was demethylated using boron tribromide. The hydroquinone
44, 47 and 50 were converted into quinone by the oxidation
of silver oxide. The quinone compounds were highly photo-
labile; it is important that extreme care must be taken to
exclude light during their synthesis as well as during sub-
sequent manipulations. Because of the thermodecomposition of
those quinone compounds, there are no molecular ions in mass
spectra.

The photovoltaic effect of these quinone compounds were
obtained on a bilayer lipid membrane. The photovoltage of
45, 48 and 51 was 230 mv, 140 mv and 139 mv respectively.

The photovoltage of zinc complex of 48 was increased to 180
mv. The photovoltage of chloroplast extract was only about
90 mv [64]. Bolton et al. [65] studied the electron transfer
effect in monolayer assemines, chlorophyll as an electrOn
donor, various quinones as acceptor. With acceptor containing
saturated side Chain, the open circuit photovoltage was lower
than that with unsaturated side chain. In compound 45 there
has a carbonyl group to conjugate with quinone, on compound
48 the conjugation was interupted by a methylene group, and
the photovoltage was dropped from 223 to 140 mv. The
inserting of the zinc metal into compound 48 decreased the

redox potential of porphyrin ring, make it is more easy for

101

electron transfer, the photovoltage increased to 177 mv.

Experimental

 

The purification of solvents and instruments were the
same as chapter 2.

The basic photoinactive membrane forming solution for
experiments is a 1 : 1.7 : 3.1 : 1.1 mixture of phos-
phatidylserine/phosphatidylcholine/phosphatidylethanolamine/
cholesterol in n-octane to a final concentration of less than
1% (W/W). Sodium ascorbate acts as donor and ferric chloride
acts as acceptor.

The technique used in the measurement of photovoltage is
essentially the same as that described previously. BLMs
solution were formed in a 1-mm aperture of a Teflon cup
separation two aqueous bathing solutions. The cup was placed
in a pyrex glass Chamber with an optical glass window.
Electrical contact between the two aqueous solutions was made
by a pair of calomel electrodes with internal salt bridges.
The photopotentials and photocurrents were measured with a
high impedance electrometer (KeithIey Model 610), with high
input to the inside BLM chamber, and connected to ground.

The membranes were formed in 0.1 M sodium acetate buffer at

PH 5. After the membrane had thinned to the black state and
its dark resistance has reached a steady value of approximately
1080, the electron donor 100 pl was added to the outside of

the membrane (facing the light source), while the electron
acceptor 100 pl was added to the opposite side of the membrane.

Then the membrane was irradiated with white tungsten light

102

(200mW/cm% to obtain the photopotentials.

2,5-Diacetyl benzoic acid 40

2,5-Dihydroxy benzoic acid 3 (500 mg) and 500 mg anhydrous
sodium acetate were dissolved in 2 ml acetic anhydride. The
mixture was refluxed for 3 hr and then poured into 50 ml water,
the pH value of the solution was adjusted to 7, and twice
extracted with ether. The ether was removed under reduced
pressure to give 700 mg of diacetate benzoic acid (91%).
p.m.r. 2.27 (s, 6H, -CH3), 7.00 (d, J = 8.0 Hz, 1H, Ha), 7.13

(d,d, J 8.0, 2.0 Hz, 1H, Hb), 7.63 (d, J = 2.0 Hz, 1H, Hc).

238.

MS: M+
(2,5-Diacetyl)benzyl chloride 41
2,5-Diacetyl benzoic acid (500 mg) was dissolved in 20
ml dry benzene, 20 ml dry ether and 1 ml thionyl chloride.
The mixture was refluxed for 5 hr and then allowed to stand
overnight at room temperature. After removal of the solvent,
a white crystal was obtained. No further purification was
necessary. MS: M+ = 256.
(2,5-Dimethoxy) phenylacetyl chloride 42
The acetyl chloride was obtained using the same procedure
as 41. MS: M+ = 204.
Preparation of secondary amine of porphyrins and chlorin
The secondary amine of porphyrins and chlorin was pre-

pared using the same procedure as Chapter 3.

Porphyrin amine 38

 

MS: 632 (M+-Bu).

Ch]orin amine 39

MS: M+ = 635.

 

 

 

103

General preparation of 45, 48, 51

The amine 50 mg was dissolved in 50 ml dry methylene
chloride and 1 ml dry triethylamine, the methylene chloride
solution of acid chloride was added in excess. The reaction
mixture was stirred for 20 min. The solution was washed with
water and passed through a silica gel short pad to remove the
unreacted acid and amine. The filtrate then concentrated and
purification on preparative TLC plate with a solvent of
methylene chloride. The amide products 45, 58 and 51 were
obtained in 60%.

Diacetyl benzene porphyrin 43

MS = 852 (M+-Bu), p.m.r. 3.50 (s, 0Ac, 6H), 6.70 (1H).
VIS: 398, 496, 536, 566, 620 nm.

Dimethoxy benzeneyporphyrin 46

MS: M+ = 867. p.m.r. 3.5 (s, 0CH, 6H), 6.0-6.9
(aromatic H). VIS: 397, 496, 530, 566, 619 nm.

Diacppyl benzene chlorin 49

MS: M+ = 855. p.m.r. 0.80 (complex, CHZCH3, unsaturated),
0.95 (t, -(CH2)3-§H3), 1.30 ('CH22fl3: unsaturated), 1.50
(-CH2£H3, unsaturated), 1.80 (COCH3, CHZCH3, saturated),

3.9-4.0 (CHZCH unsaturated), 4.5 (broad, CHCC), 6.7-7.2

39
(aromatic H).

Hydroqginone porphyrin 44

 

50 mg of43 was dissolved in 10 ml dry methylene chloride
and mixed with 10 ml of HCl saturated methanol. The mixture
was heated on a steam bath for 20 min. The solvent was

removed on a rotary evaporator and the residue dried in vacuo;

104

35 mg of dihydroxybenzene porphyrin was obtained. VIS: 398,
496, 530, 565, 620 nm.

Hydroquinone porphyrin 47

100 mg of porphyrin 46 was dissolved in 50 ml dry
methylene chloride with stirring in a dry ice acetone bath.
2 g boron tribromide in 10 ml methylene chloride were added
dropwise. The reaction mixture was stirred at -78°C for 5 hr
and then warmed up to room temperature. It was kept stirring
for another 2 hr before 10 ml water was added over a 10 min
period to terminate the reaction. The organic layer was
passed through a silica gel pad; the front fraction was dis-
carded. The pad was then washed with 10% methanol/methylene
Chloride solution to collect the dihydroxy benzene porphyrin
(yield 60%). MS = 631. VIS: 393, 496, 532, 564, 616.
p.m.r. 6.1 (complex, aromatic H).

Hydroquinone chlorin 50

 

This compound was obtained as 44. VIS: 395, 495, 590,

644. MS: N* = 772. p.m.r. 6.8 (broad, aromatic H).
General procedure for the preparation of quinone por-

phyrins 45, 48, 51

 

The dihydroxybenzene porphyrin (20 mg) was dissolved in
20 ml dry THF. Anhydrous magnesium sulfate 1 g and 0.5 9 silver
oxide were added to the solution. The mixture was stirred in
dark for 30-40 min. The reaction mixture was then passed
through a silica gel pad to remove the solid and unreacted
dihydroxy benzene porphyrin. The quinone porphyrin 45, 48
or 51 was obtained with about 85% yield.

105

Quinone porphyrin 45
v15: 398, 498, 524, 556, 620 nm. IR: 1640, 1660 cm“.
MS: decomposed.

Quinone porphyrin 48

VIS: 397, 496, 532, 563, 616 nm. IR: 1600, 1630,
1660 cm'l. MS: M2 = 631. p.m.r. 4.87 (s, 2H, methylene H),
6.0 (complex, 2H), 6.5 (complex, 1H).

Quinone chlorin 51

VIS: 392, 488, 496, 522, 590, 644 nm. IR: 1615, 1670

cm'l. MS: decomposed. p.m.r. 6.6-7.2 (aromatic H).

10.

11.

12

13.

14.

15.

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