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This is to certify that the

thesis entitled
THE SYNTHESIS AND CHARACTERIZATION
OF MODELS FOR HEME—CON'I'AINING PROTEINS

presented by

Richard Hall Young

has been accepted towards fulfillment
of the requirements for

Ph.D. Chemistry

degree in

 

 

Major professor

44; z: a”
at

DateJ’Gli “$4 WW

0-7639 MSU is an Affirmative Action/Equal Opportunity Institution

 

 

 

‘ RETURNING MATERIALS:
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returned after the date
stamped below.

 

 

 

 

 

 

 

THE SYNTHESIS AND CHARACTERIZATION OF MODELS FOR

HEME-CONTAINING PROTEINS

By
Richard Hall Young

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry
1986

 

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by

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A '1
’.IA“7‘,I': v"

Kr“ ,1 ,-

ABSTRACT

THE SYNTHESIS AND CHARACTERIZATION OF MODELS FOR
HEME-CONTAINING PROTEINS

By
Richard Young

The synthesis of a series of blocked and imidazole appended di-
phenylporphyrins is described. The hybrid porphyrin is synthesized
by the condensation of o-nitrobenzaldehyde with 4.4'-diethyl-3,3'-
dimethyl-Z,2'-dipyrrylmethane in methanol followed by oxidation and
reduction. The effectiveness of the blocking groups is supported
by the formation of stable ferric hydroxides in the doubly protected
system; trans 5,15-bislo-(p-t-butylbenzamido)phenyl)-2.8,12,18-tetra-
ethyl-3.7,13.l7-tetramethylporphyrin. This complex was characterized
by UV-visible, 1H NMR, IR, and cyclic voltammetry. The ability of the
m-benzamido linkage to enforce imidazole coordination is shown by 1H
NMR studies on the ferric bis imidazole complexes of free, and
covalently linked systems.

The diphenyl porphyrins are also used in the construction of
binuclear systems. including a mixed cofacial diporphyrin. The
effectiveness of chelating ligands is supported by electron spin
resonace studies.

Synthetic analogues of hydroporphyrins are constructed from
gemini-alkylated ketones resulting from the oxidation of octaethyl
porphyrin. The synthesis of simple chlorins, bacteriochlorins,
isobacteriochlorins, and imidazole linked systems are described.
These stabilized hydroporphyrins are fully characterized by UV-

visible, 1H NMR, and cyclic voltammetry.

To Dad, Mom
George. Leonard, Martin,
Robert. Kathy,
and Jim.

ii

ACKNOHLEDGHENTS

The author would first of all like to thank his parents and
family for their never ending support and understanding. The
author is also indebted to Dr. C.K. Chang for his support and
guidance. Gratitude is also extended to Dr. R.H. Fish for his
foresight and compassion. I am also grateful to Michigan State
University, the National Science Foundation, and the National
Institute of Health for the opportunity and freedom to complete
this research.

A Special thanks is also extended to all those who made my
stay worthwhile: Brian, for teaching me how to laugh at myself;
Ivy, for intiating and enduring a friendship; Susan and Nancy,
for helping me tread that fine line; and (MAM)X2, for caring
enough to fight back. In addition; Steve, Larry, Steve, Paul,
Steve. Tim. and the rest of the Megahurtz, Aromatics, Zero's,

and Alkanes for making winning and losing so much fun.

iii

TABLE OF CONTENTS

LIST or TABLES .1. . . . . . . . . . . . . . . . . . . . . . . . .
LIST OF FIGURES O O O O 0 O O O O O 0 O O 0 O O O 0 o O O O O O 0
LIST OF APPENDIX FIGURES . . . . . . . . . . . . . . . . . . . . .
CHAPTER 1: The Synthesis and Characterization
of Blocked and Ligand Appended Hemes
Derived from Atropisomeric Diphenyl
Porphyrins
humanflmi. .... .... .... .... .... ...1
synthQSES O O I O O O O O O 0 O O O O O O O O 0 O O O O O 0 2
Thermal Atropisomerization . . . . . . . . . . . . . . . . . 13
1H NHR of Free Base Porphyrins . . . . . . . . . . . . . . . 15

Electronic Spectra . . . . . . . . . . . . . . . . . . . . . 19

1H NMR of Iron Porphyrins . . . . . . . . . . ..... . . . 19
Sterically Protected Hemes and Hydroxide

Formation . . . . . . . . . . ............. . . 23
Hemes Appended with Imidazoles .......... . . . . . 34
p-Ketoamide Appendages . . . . . .......... . . . . 45.
Phenolic and Ester Linked Diphenyl ............. 46
Summary and Further Studies . . . . . ........ . . . . 47

Exmr‘mnu] O O O O ' O O O O O O O O O O O O O O O O O O O O .48

CHAPTER 2: The Synthesis‘and Characterization of
Multinuclear Systems Derived from
Diphenyl Porphyrins

Introduction ..................... . . . 75
Dimers . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Synthesis . . . ..................... 77
Absorption Spectra. ................. . . 78

iv

1“ “HR 0 O O O O O O I O C O O O O O O O O O O O O O O O

ESR. Natal-Metal Interactions. . . . . . . . . . . . . .
Porphyrins with Hetal-Chelatins Appendages . . . . . . . .
Synthesis ...... . ........ . . . . . . . . .
1H nun . . . . . . . . . . . . . . . . . . . . . . . . .
Electronic Spectra . . . . . . . . ...... . . . . . .
ESR. Binuclearsystems . . . . . ....... . . . . . .
Conclusions and Further Nork . . . . . . . . .......
Experimental . . . . . . . . . . . . . . . . . . . . . . .
CHAPTER 3: The Synthesis and Characterization
of Simple and Derivatized Geminal
Alkylated Hydroporphyrins
Introduction . . . . . . . . . . . . . . . . . . . . . . . .

Oxidation-Reduction . . ..... . . ....... . . . . .

Ligand'Appendedsysmsoooooooosooeooooooo

Absorption Spectra . ............... . . . . .
1H NHR . . . . . . . . . . . . . . ..... ; . . . . . . .
Cyclic Voltammetry . . . . . . . . . ........... .
Hetal Insertion and Coordination Studies ..... . . . . .
Ferric Hydroporphyrins. Alkaline Form ........... .

Experimental........................
APPENDIX . . . . . . . . . . . . . ...............
REFERENCES . . . . . . . . . . ............ . . . . .

80
82

88
92
101
101
103
107

116
117
121
125
130
140
143
147
153
169
238

LIST OF TABLES

Table No. Pa No.

Table 1. Blocked and Ligand Appended Diphenyl
Porphyrinsooo....OOOOOOOOOO...OOOOCOOOOOOOOOOOOOOO. 3

Table 2. C0 and 0 Binding Constrants of Diphenyl
Hemes wi‘h Remote Polar Croups..................... 11

Table 3. CO and 0 Binding Constrants of Diphenyl
' Hemes wiih Groups of Varying Polarity
Situated Near the Ligand Binding Site.............. 12

Table 4. Rate Constants and Activation Parameters
for the Thermal Atropisomerism of Diphenyl
Porphyrins and Related Tetraphenyl Porphyrins...... 15

Table 5. Electronic Spectral Data of Selected

Free Base Diphenyl Porphyrins...................... 20
Table 6. Electronic Spectral Data of Selected

Iron (III) Diphenyl Porphyrin Complexes............ 21
Table 7. Observed NHR Shifts of Protons in

. Selected Ironillllillll Diphenyl

Porphyrin Complexes.................. .............. 24
Table 8. Electronic Spectral Data of Selected

Gemini-Alkylated Hydroporphyrins ..... .. ............ 126
Table 9. Redox Characteristics of Selected

Gemini-Alkylated Hydroporphyrins... ............. ... 141

LIST OF FIGURES

Figure No. --, Page No.

Figure 1. Comparative 250 MHz 1H NHR spectra
of derivatized diphenyl porphyrins;
(A) (aminoIZDPE. trans (I); (8)
(amino). (P-tBu-benzamidElDPE, trans
(fi); (C) (P-tBu-benzamide) DPE, trans
( ); (D)(p-tBu-benzamide)2 PE. cis
10k (EHp-tBu-benzamide). (m-ImCHZ
b5hzamide)DPE, trans (g1).......................... 16

Figure 2. Effect of solvent on the resonances
for the aromatic protons of the blocking
group in (p-tBu-benzamideIZDPE. cis (10).
A - CDC13. B - DHSO-ds...............?7............ 18

Figure 3. Electronic spectra of Fe(III)Pc1 com-

plex of (p-tBu-benzamidelzoPE. trans
(2) (---); and the effect of adding
excess imidazole (--)............................ 22

Figure 4. Electronic spectra of FeiIII) com-

plexes of (p-tBu-benzamide) DPE. cis

(19); FeiIIIlPCI (....i; FeIIIllPDN

(----);Fe(III)P20 (--)............ ....... . ....... 27
Figure 5. Cyclic voltammograms of FeiIII) com-

plexes of ( -tBu-benzamide)2DPE. (a)
cis,‘Fe(III P 0; (b) trans, FeiIII) -
PCI; (c) trang, FeiIIIlPDH...... ............... .... 23

Figure 6. Infrared spectra of FeiIII) complexes
of (p-tBu—benzamide) DPE, in CCI , (a)
solvent; (b) trans. EelIIIlPC1; Ic)
trans. FeiIII)POH; (d) cis, FeiIII)P20..... ..... ... 29

Figure 7. 250 MHz 1H‘NHRspectra of FeiIII) com-
plexes of (p-tBu—benzamidelzoPE, cis
(12) and trans L2) in CDC13 at 22'C................ 31

Figure B. Curie plot for the Fe(III)POH complex
of diphenyl porphyrin 2;............. ...... ........ 32

vii.

 

fl

n1

Fig

Figure 9.

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

10.
11.
12.
13.
14.

15.

16.

17.

18.

Electronic spectra of (FeiIII) come
plexes of (p-tBu-benzamide)DPE. (a)
trans. Fe(III)POH (----l; and the
effect of adding excess imidazole (--).
(bl cis. FeiIII P0 (----); and the
effect of adding Excess imidazole (--)

Temperature dependent 1H NHR spectra of
FeiIII)PC1 complex of (acetamide) DPE.
trans (*3) containing 2 equivalenés
I-methy imidazole in CDC13.. ............

Temperature dependent 1H NHR spectra
of the FeiIIIIPIm C1 complex of
(ImiCHzl 3NHCDNle PE. trans (11) in

.CDC13ooooooooooooo ooeeoooooooooooo .......

Temperature dependent 1H NHR spectra
of the FeiIII)PIm C1 complex of
(m-IMCH benzamide DPE. trans (11) in
2 2
C0C13n.. o .0 00.000000000000000

1H NMR spectrum of the FeIIII)PImC

complex of (p-tBu-benzamide). (m-ImCHZ
benzamideloPE, trans in CDCI3 with
excess imidazole. ..... .......... ... .....

Electronic spectra of C dimethyl

ester (49) (.. ); (amigo) DPE, cis

(2 (----l; and mixed dipogphyrin 50 .
--), in CHZCI2 ........................

250 NH 1H NHR spectrum of mixed

diporpfiyrin §g in CH2C13.. ... ............

ESR spectrum of Cu(II)-Cu(II) complex
of mixed diporphyrin 0 in frozen
solution (51 toluene/C 2C12) at 77'K .....

ESR spectrum of dioxygen adduct of

bis cobalt complex of diporphyrin 6g

at room temperature after addition of

a small amount of 12. ....................

250 MHz 1H NHR spectra of chelating

diphenyl porphyrin 51 in (A) CHZC
containing trifluoroacetic acid, (a)

m§13;(C) toluene- d8, all spectra
ed

22' C ............................

viii.

...... ..... 35

.......... 38

.0... ..... 41

.......... 42

...... O... 44

.......... 79

.......... 81

.......... 83

.......... 85

.......... 93

Figure 19.

Figure 20.

Figure 21.

Figure 22.

Figure 23.

Figure 24.

Figure 25.

Figure 26.

Figure 27.

Figure 28.

250 MHz 1H NNR NHR spectra of trinuclear

diphenyl porphyrin 52 and precursors,

(at R- H, R' - caz;“lb) R-R' - H;

(C) R‘R. . cuchZEtoeoooeooeoeooeoeecoooooooeooeooo 97

250 MHz 1H NHR spectra of blocked and

chelating diphenyl porphyrin 53 and

precursors. (A) RsH ,R'- -tBoc; (B)

R- R' - H; (C) R- R' -CH2C02Et........... ......... . 99

250 MHz 1H NHR spectra of imidazole

appended and chelating diphenyl

porphyrin 54 and precursors. (A)

R - H. R' - ~CBz; (B) R- R' 8 H..................... 100

Electronic spectra of the Fe(III)PC1

complex of diphenyl porphyrin a; (--);

and the effect of adding Cu(II) acetate

to the sample (----).................... ....... .... 102

ESR spectra of blocked and chelating

diphenyl porphyrin 3, (A) Cu(II)

porphyrin-diacid; (B Cu(II)-Cu(II)

complex. Spectra measured in frozen

solution (51 toluene/CH2612) at 77'K. ...... . ...... . 104

ESR spectra of blocked and chelating
diphenyl porphyrin S1, (A) Ni(II) porphyrin-
acid; (8) Ni(II) porphyrin Cu(II) complex.
Spectra measured in frozen solution (5! .
toluene/CHZCIZI at 77°K...... .................. .... 105 ,

ESR spectra of blocked and chelating

diphenyl porphyrin 6;, (A) Fe(III)PC1-

diacid; (B) Fe(III)PCt-Cu(II) complex.

Spectra measured in frozen solution

(51 toluene/CHZCIZ) at 77'K........................ 106

Hydrogen bonding in chlorin and
isobacteriochlorin ethyl acetate-alcohols ...... .... 125

Electronic spectra of monoketone 66 (--);
and methyl chlorin alcohol 77 (----).. ......... 127

Electronic spectra of 2, 6 diketone 70

(--); and alkylated products; mono-

alkylated (----); bis alkylated bacteriochlorin

81 (....) ........ . .............. ................... 128

~

ix.

 

Fl

Fi

Fig

rig]

Figurev29.

Figure 30.

Figure 31.

Figure 32.

Figure 33.

Figure 34.

Figure 35.

Figure 36.

Figure 37.

Figure 38.

Figure 39.

Electronic spectra of 2. 3 diketone 68
(97-); and alkylated products; mono~
alkylated isobacteriochlorin 95 (....);
bis alkylated isobacteriochloFIn 13

---- ooooaooooooo-oooooeoeeooooeoooooooooeoooooooo 129

Electronic spectra of reduced 2. 6
bacteriochlorin 83 (----); and effect
of exposure to light (--)........................ 131

1H NHR spectra of methylene bacterio-
chlorins; (A) (R. R') - CH2 (8;); (B)
R . CH3. R. . 0H (gg)oooeooooeoooooooooooooooo ooooo 133

ORTEP representation of 2, 6 dimethylene
bacurIOChIOrin 13’...OOOOOOOOOOOO00.000.00.000..00. 134

1H NHR spectra of diasteriomeric 2. 6
dimethyl gemini octaethylbacteriochlorin
alcohols (81); (A) trans; (B) cis........... ..... .. 135

1H NHR spectra of imidazole appended
chlorin 93; (A) in CDC13; (B) CDC13-TFA..... ....... 136

1H NHR spectra of imidazole appended
chlorin 93; (A) free base, H - 2H; (8)

MaznOOOOOOO......OOOOOOO00.0..........OOOOOOOOOOO138

1H NHR spectra appended chlorin 83
showing effect of increasing dilution;
lowest trace most concentrated......... ....... ..... 139

Cyclic voltammograms of gemini-alkylated
hydroporphyrins derived from OEP; (A)

chlorin 18; (B) isobacteriochlorin 89;

(C) bacteriochlorin 83. Spectra measured

CH C1 with (Bu)4NC104 as supporting

elzct olyte........................................ 142

Possible orientations for intramolecular
coordination in the zinc complex of
appended chlorin Bg...................... .......... 144

Electronic spectra of the ferric chloride

complex of methyl octaethylchlorin Lg

(--); effect of adding Et N or 25% aq.

neon §----); effect of addigg (Bu)4N0H 45
.... .......... ................... ....... ..... .... 1

Figure 40.

Figure 41.

Figure 42.

Figure 43.

Figure 44.

Figure 45.

Figure 46.

1H NMR spectrum of paramagnetic ferric
chloride complex of methyl octaethylchlorin........ 146

1H NHR spectra monitoring the addition

and reaction of 00 [020 to Fe(111)C1

complex of chlorin 19° (A) Fe(111)C1.

no base; (8) 10 min. after addition of

base; (C) 20 min. after addition, com-

plete conversion to alkaline form.................. 148

Comparison of 1H NMR spectra of Fe(111)
complexes of chlorin 78; (A) chloride; (8)

~

“alkaline form“; (C) (J-oxo dimer.................. 149

' Possible structure of highly symmetrical

ferric hydroxides resulting from solvation......... 150

1H NMR spectra monitoring the addition

and reaction of 00 ID 0 to Fe(111)C1

complex of octaethyl Sorphyrin. (A)

Fe(111)C1. no base; (8) 10 min. after

addition of base; (C) completion of

reaction, }J-oxo dimer................. ........ .... 151

1H NMR spectra monitoring the addition

and reaction of 007D 0 to Fe(III)Cl

complex of tetraphengl porphyrin. (A)

Fe(111)C1, no base; (8) 10 min. after

addition of base; (C) completion of ,

reaction, (J-oxo dimer............................. 152

1H NMR spectra monitoring the addition

and reaction ofOD ID 0 to Fe(111)C1 com-

plex of etioporphyrifi. (A) Fe(III)C1,

no base; (8) 10 min. after addition of

base. mixture of alkaline and 'J‘OXO

dimer; (C) complete conversion to lJ-oxo
dimer.............................................. 153

xi.

Figure
A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

. LIST OF
APPENDIX FIGURES

Page

so nu: 1H van spectrum of 4.4'diethy]-
3.3"dlfl¢th¥l-2.2'-dipvrrluethan¢ (g)............ 159

250 MHz 1H NMR spectra of (a) (nitro)
DPE (4); (b) (nitro)ZDP etioporphyrinSgen........ 170

250 "Hz 1H NMR spectra of (a) (amino).
(m-BrCHZbenzamide)DPE. cis (6); (b)
(m-BrCszenzamide)20PE. cis:?1................... 171

250 "Hz 1H NMR spectra of (amino).
(m-Im-Cszenzamide)DPE; (a) trans (1); (b) cis

8 00.00.00.0000000...0.00............0000000000. 172
~

250 "H: In NRA-spectra of (m-Im-Cszen
zamide) DPE; (a) cis (12);
(b) trig: (L1)00000000:00000.00.00.000000000000. 173

250 MHz 1H NMR spectrum of (acetamide)z OPE.
trans (g)00000000000000000.0 ..... 0.0.0.000000000174

250 MHz 1H NMR spectra of bis alkyl linked

ops; u-zu; (a) (ImCH ) uncoun) ope. trans

(1;); (b) (ImCH )3coiui one. tFans (15);

(c (1nCH212couK)zoPE. (ran: (1g)...f?...... ..... 175
250 "H: 1H NMR spectra of (a) (Br(CH )3-

COMM) DPE, trans (18); (b) lactam ((8H213-

N)ZDP , trans (39)CTZ. ........................... 176

250 MHz 1H NMR spectrum of (m-NME3CH2-
benzamide)ZDPE. trans (g1) .......... . ........... . 177

250 "Hz 1H NMR spectra of phenolic por-
phyrinogens; (a) R - Me; (b) R a H.... ..... . ..... 178

250 MHz 1H NMR spectrum of (hydroxy)2
OPE, trans (gg)........... ....................... 179

250 MHz 1H NMR spectrum of (hydroxy)2
DPE,cis (g3)... .................................. 180

250 MHz 1H NMR spectrum of (p-tBu-ben-
zoate)zDPE, trans (24) ....................... .... 181

xii.

 

Al

Al

Al

Al

Al

Al

A2

A2

A2

A2

A2

A2

A2

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

250 "Hz IH NHR spectrum of ((m-ImChz-ben-
zoate)2DPE. trans (£5).............. ............ . 182

256 M": In RMR spectra of (a) (m-BrCH -
benzamide).(P°t8u-benzamide)DPE. trans

(2%); (b) (m-AcSCszenzamide).(p-tBu-benzamide)
DP . trans (28).................................. 183

250 MHz 1H NMR spectra of (p-tBu-benz-
amide).(m-1mCH benzamide)DPE, trans (27);
(a) l" CDc13; eh) coc13 + TFA eeeeeeee freeeeeeeeoe 184

250 MHz 1H NMR spectra of (a)(p't8u-benzamide).

. (I.(CH2)3CONH)ZDPE3 trans (29)eeoeeeooeeeeeeeeeee 185

250 MHz 1H NMR spectrum of (p-tBu-benz-
amide).(1m(CHZ)3NHCONH)DPE, trans (31)........... 186

250 MHz 1H NMR spectra of trans blocked

(m-ImCszenzamide)DPE; (a) R - n-Bu (34);
(b) R . Et (33).................................. 187

250 MHz 1H NMR spectrum of (3,5(CONH

-nBu)2benzamide),(m-Im-Cflzbenzamide)DPE.
trans (%)000000.00...00000000 000000000000 00.0.0.188

250 MHz 1H NMR spectra of trans benz-
amide blocked (m-Im-CH benzamide)DPE;
(a) R . iPr (;g); (b) fi . it (13). ..... - .......... 189

250 MHz 1H NMR spectrum of (3,5(cos-
n8u) benzamide),(m-Im-Cszenzamide)DPE,
tran; (31)...... ................................. 190

250 MHz 1H NMR spectrum of (3,5(cuzou)
benzamide).(m-Im-Cszenzamide)DPE, trags
(g3)00000000000000000 0000000000000000000000000000 191

250 MHz 1H NMR spectrum of (3,5(cnzone)
benzamide),(m-Im-CHZbenzamide)DPE. trang
(33) 0000000000 .0000 000000000000000000 00. ........ 0 192

250 MHz 1H NMR spectra of (m-NMe CHZ-benzamide).
(mrIm-CH benzamide)DPE, trans (fig); (a) in
coc13; (6) cm3 + TFA ....................... .... 193

250 MHz 1H NMR spectrum of (m-NMe CH2~benzamide).
(m-Im-Cszenzamide)DPE, trans (41 ...... ......... 194

xiii.

A27
A28
A29
A30

A31

A32
A33

A34

A35

A36
A37

A38

A39

A40

A41

250 "Hz 1H NMR spectrum of (m-NMe CHZ-benzamide).
(m-Im-CHZbenzamide)DPE. trans (437............... 195

250 "Hz 1H NMR spectra of (acetamide),
(m-Im-Cszenzamlde)DPE. (a) trans (43);.... ...... 196

250 MHz 1H NMR spectrum of malonamide
blocked, imidazole appended DPE 45.... ........... 197

250 MHz 1H NMR spectrum of t8u malon-
amide blocked, imidazole appended DPE 46 ......... 198

250 MHz 1H NMR spectrum of dimethyl
malonamide blocked, imidazole appended
DPE 470... 00000000000 .0 000000 0.0.0.0. 0000000000 0.199

250 MHz 1H NMR spectrum of (amino)zD
etiochlorin, cis (48) ....... ............ ......... 200

Electronic spectrum of (amino)2DP etio-
ch‘orin. C‘s‘4’?!)0000000.0.0000000000000.00...... 201

250 MHz 1H NMR spectrum of (amino). (1m-
(CHZ)ZCONH)DPE. tranSeeeeeeeeeeeeeee eeeee e eeeeee e 202

250 MHz 1H NMR spectra of the Fe(III)PC1
complexes of alkyl appended imidazole
DPE; (a) n = 3 (39); (b) n a 2 (23).............. 203

250 MHz 1H NMR spectrum of the Fe(11)-
PImCO complex of doubly protected DPE 1Q......... 204-

250 MHz 1H NMR spectrum of the Fe(II)-
PImCO complex of imidazole appended DPE 31 ....... 205

250 MHz 1H NMR spectra of the Fe(II)PImC0
complexes of imidazole appended DPE; (a)

R = m-ImCHZ (11); (b) R = p-tBu (2])... .......... 206
1H NMR spectra monitoring the conversion
of Fe(111)PC1 to Fe(III)POH in OPE 19 ............ 207
ESR spectra of Fe(111) complexes of DPE
10; (A) FePCl; (8) FePOH. 771K in CH2C12.. ....... 208
Temperature dependant 1H NMR spectra of
the Fe(III)P1m2C1 complex of DPE 13 .............. 209
N

xiv.

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

Temperature dependant 1H MIR spectra of
the Fe(111)P(benzyl 1m)zC1 complex of

D.PE B00000...00.0000....000.000.0000...00000....

Temperature dependant 1H NHR spectra of
the Fe(111)P(1-HeIM)2C1 complex of

D ~00000000000000000000000.00.0...00000000000.

Room temperature 1H MR spectrum of the

Fe(111)P1m2C1 complex of etioporphyrin...........

Room temperature In NHRspectrum of the
Fe(111)P1m2C1 complex of (m-Im-Cszenz-

““7209E, trans (§)mmeeeeemeeeemeeeeeeeeeeeeeee

60 MHz 111 um spectrum of m-( oL-bruo)

to‘uoy‘ chloride.0000000000000.000.00.000000000.0

60 MHz 1H NMR spectrum of 3.5 (BrCHz)z'

benZO‘c Reid 000.00.000.0000000.0.00.00.00.000000

60 MHz 18 NMR spectrum of the monomethyl

esur 0f dip1c011n1c ac1d0000000000000.0.0....00.

60 MHz 1H NMR spectra of methyl 2-( )9 -

carboxyl)acetylpyridine-6-carboxylate............

Electronic spectrum of the Fe(111)POH
complex of bisaminodiacetic acid DPE

531" "aur00..0000.0.0000000000000000. ..... .0...

250 MHz 1a nun spectra of (a) (a. R') . o.
monoketone 66' (b) R - CHZCOZEt,
R' -0H.ch13?n§g......... ....... . .......... .

250 MHz 111 um spectrum of alkylated

chlorin 86............... ........... .. ....... ....
H

250 MHz 1H um: spectrum of methylene

alkylated chlorin 85................. ....... ... .
N

250 MHz 1H NMR spectrum of the zinc

complex of 2, 6 diketone ZQ.....................

250 MHz 1H NMR spectrum of alkylated
baCteriOCh‘orin g‘eOOOOOOOOOOOOOOOOOOOO0.000.00.

250 MHz 111 um: spectrum of amide linked

imidazole chlorin 89........ ..... ..............
, N

XV.

0

210

211

212

213
214
214

215

215

216

217
218
219
220
221

222

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

250 H": 1H nun spectrum of uittig
generated chlorin 99,............... ...... ....... 223

250 AH: 1H NMR spectra of alkylated
chlorins (a) R - CHZCOZEt (gg); (b)
R . CHZCHZOH (93,000.00000000000000000eeeeoeeeoem 225

250 MHz 1H NMR spectrum of ester linked
inidQZOIQ cu‘orin gOOOOOOOOOOOOOOOOOOOO00.0.0.0. 226

250 MHz 1H nun spectra of (a) (n. R')
' 0. 2, 3 diketone 68; (b) R 3 OH. R.
- He. isobacteriochlarin gg.............. ..... ... 228

250 MHz 1" nun spectra of alkylated
isobacteriochlorins; (A) R - 0H (96);
(B) R.“ (2g)...oeeeeeeeeeeeeeoef‘e’eeeeeeeeeeeeo. 229

250 MHz 1H nun spectra of alkylated
isobacteriochlorins; (A) R a H (192);
(b) a - cocnzcnzim (191)...............;......... 231

250 14112 1H mm spectrum of alkylated
iSOb‘CterioCh10r1n 9~700000000000000000000.0.0.... 232

so MHz 1H unR spectrum of 3-(N-imid-
azolyl)propylamine. neat......................... 233

so MHz 1H NMR spectrum of N-acetyl
3-(N0imidazoyl)propylamine. 020.................. 233

60 MHz 1H NMR spectrum of N-isopropyl
3-(N0imidazolyl)propylamine, 020....... ........ .. 234

60 "H: 1H NMR spectrum of N-acetyl N-
isopropyl 3(-N-imidazolyl)propylamine............ 234

60 "Hz 1H NMR spectrum of methyl 3-
(N-imidazolyl)proprionate, neat.................. 235

60 MHz 1H NMR spectrum of ethyl 2-(u-
imidazolyl)acetate. CDC13............ ..... ....... 235

60 MHz 1H van spectrum of 4-(N-imid-
azolyl)butyronitrile, neat...... ................. 236

60 MHz 1H NMR spectrum of 4-(N-imid-
0101,17b0tyric “Cid. 020 eeeeeeeee me eeeeeee 0000000 236

xvi.

A72 Cyclic voltammograms of (A) tetraphenyl
porphyrin; (8) tetraphenylchlorin; (C)
zinc - TPC; (D) tetraphenylbacterio-
chlorin. Spectra measure in CH2C1 w/
(Bu)4NC104 as supporting electrolyge. ........ .... 237

xvii.

CHAPTER 1

THE SYNTHESIS AND CHARACTERIZATION

OF BLOCKED AND LIGAND APPENDED HEMES

DERIVED FROM ATROPISOMERIC DIPHENYL PDRPHYRINS

Rh

96:

Introduction

 

The construction of synthetic metalloporphyrin complexes which
mimic heme-containing proteins has been one of the most powerful
methods in studying reaction mechanisms and structure-function
relationships of hemoproteins. Most model systems are based on two
families of porphyrins; the p-substituted porphyrins (e.g. proto-
porphyrin) and the mesa-substituted tetraphenyl (TPP) derivatives.
These two types of porphyrins have been manipulated extensively and in
the last decade a large number of interesting model systems with
colorful names have been created. 1'4 The p-substituted compounds
resemble more closely the naturally occurring hemes, however, the
excessive floppiness of the side chains used in functionalization is
often undesirable. The tetraphenyl systems, particularly those
functionalized with o-anilido groups (e.g. "picket fence" heme). are
structurally more rigid. Nevertheless, they suffer from the fact that
synthetically it is very difficult to derivatize one particular phenyl
group (out of four in TPP) on the prophyrin ring in order to attache

special appendages. Recently, Gunter and Mander 5

reported the
synthesis of a hybrid meso-diphenylporphyrin. This system appears to
be attractive for model building purposes in that the atropisomers of
the o-amino substituted derivative can be separated and manipulated
individually to yield a wide variety of useful heme model compounds.
While these authors described the synthesis of heme-copper complex

5.6

based on one of the atropisomers no other work has been reported

Ni

exploiting this useful system. 'He describe here an improved synthesis
of this hybrid porphyrin as well as a large number of protected and
chelated heme model compounds that can be derived from this porphyrin.
The diphenyl porphyrins 1 and 2: substituted with ethyl and methyl
groups are easier to synthesize and are substantially more soluble in
organic solvents than the octamethyl analogue. The ring methyl groups

in this system hinder the rotation of the neighboring phenyl rings

allowing isolation of the atropisomers. This steric constraint and
the conformational rigidity of amides can be employed to enforce
selective ligation and/or blockage of the porphyrin coordination site.
Our synthetic targets summarized in Table 1, demonstrate that a large
number of novel porphyrins capable of tetrapenta-, and hexa-coordina-
tion can be generated conveniently using this approach. These
synthetic hemes have been applied in modeling studies of 02 and C0
binding in hemoglobins and myoglobins.
Synthesis
The parent compound, 5, 15-bis(o-aminophynyl)-2,8,12,18-tetraethyl

3,7,13,17-tetramethylporphine, or (NH2)2-DPELamina-dipheny1
etioporphyrin II) was synthesized by condensation of equivalent
amounts of 5, 5'- unsubstituted dipyrrylmethane 3: and o-nitrobenzal-
dehyde in methanol with a catalytic amount of p-toluenesulfonic acid,
Scheme 1. The resulting porphyrinogen 4: was oxidized with
o-chloranil and reduced to the corresponding atropisomeric diamino
porphyrins. The prerequisite decarboxylation of the dipyrrylmethane

was found to proceed readily in one step from its diester precursor.

 

 

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In contrast. the tetramethyldipyrrylmethane used by Gunter and Mander5

was notoriously difficult to prepare and required a bomb reactor to
effect decarboxylation. In the present scheme, the yields were better
than 70% in each step. The diamino prophyrins have good solubility in
organic solvents and separation of atropisomers can be carried out
directly in large scale on silica gel columns. The isolated indi-
vidual atropisomers were found to be conformationally rigid, only
under prolonged heating at >100°C could they be thermally equilibrated
to 1:1 mixtures of cisztrans isomers. The activation energy needed
for thermal interconversion of the two isomers was found to be 26.2
Kcal/mol for the parent diaminoporphyrin and 28.8 Kcal/mol for the
acetamido derivative. The rotational barrier and conformation of the
amides should allow attachment an direction of specific groups over
the prophyrin core. These groups can serve a wide variety of func-
tions and be readily modifiable without causing severe changes in the
overall complex.

To prepare anilido derivatives, the most efficient method was
found to be direct coupling between acid chlorides and the aminopor-
phyrins. The yields were routinely >602 when the acid chlorides could
be isolated. In cases where the acid chloride could not be isolated,
we have employed with success ethyl chloroformate and trifluoroacetic
anhydride in mixed anhydride couplings. The symmetrically substituted
anilides were initially constructed to develop the required synthetic
methods and aid in the characterization of more complex systems.

A simple soluble protected porphyrin can be constructed by

treating the trans diamine l. with an excess of p-t-butylbenzoyl
chloride. The resulting trans (p-t-butylbenzamido)2 DPE 9 isolated in
> 90% yield, possesses phenyl rings held above and below the porphyrin
ring. The protons of these phenyl groups were shifted upfield, 6.42
ppm (CDC13). and appeared as a singlet in the 1H NMR in a variety of
solvents. The more crowded cis isomer, formed by the same sequence,
showed the expected AB quartet for the phenyl protons in CDC13. bUt a
singlet in DMSO'da. These results imply that the free rotation
necessary to equilibrate the protons was restricted by solvation or
aggregation in the cis, but not in the trans atropisomer.

A series of penta-coordinate ferrous hemes were constructed
employing a stepwise coupling strategy (Scheme 2).

These differently appended systems needed in kinetic studies would
reveal the possible importance of the imidazole preequilibrium,

Equation 1, in 02 and CO binding, Equation 2.

CD + m ..___-———-. m
I
Im

0

® + 02§====3 (.sz (2)

Im Im

 

Scheme 2.

 

 

 

 

 

 

11
al

f0

Reaction of porphyrin l with one equivalent of p-t-butylbenzoyl
chloride followed by separation on silica gel yielded an almost
statistical distribution of mono, di, and unsubstituted amino
porphyrins. The mono-substituted porphyrin E: can be easily appended
with appropriate imidazole ligands. Initial attempts to generate the
alkyl liinked imidazoles throught the bromo alkanoic anilides failed
due to rapid lactam formation on treatment with base. Imidazole
alkanoic acids were successfully synthesized and coupled by procedures
analogous to those used in the synthesis of "tailed picket fence“
porphyrins.7
There is evidence indicating that appended imidazoles via alkyl
linkages are somewhat undisciplined and tend to form mixtures of bis-,
mono-, and un-ligated ferrous hemes under many circumstances.7 To
overcome this randomness, a more orientation specific imidazole
linkage was designed. The benzamide linkage is more rigid and should
also serve as an effective blocking group, preventing iJ-oxo dimer
formation in ferric hemins. This linkage was constructed by coupling
m-bromomethylbenzoyl chloride with the anilino porphyrin 23 followed
by substitution with sodium imidazolate in acetonitrile. This two
step sequence overcame the low solubility problem of
m-(ch(N-imidazolyl)toluic acid. The benzyl halides formed were prone
to hydrolysis during work-up in the presence of organic bases. This

could be prevented by simply reacting the benzyl halides in situ.

Preliminary results on the C0 and 02 association rates indicate
the affect of changing appendages is small and is of the same order
for both C0 and 02,

Modifications of the blocking group near the ligand coordination
site (trans to the imidazole) were made in order to model the polarity
and steric effects inside the myoglobin heme pocket. The mono-benzyl-
imidazole porphyrin/Z was easily prepared by treatment of the diamino
DPE with one equivalent of X-bromotoluic acid chloride, followed by
addition of sodium imidazolate in acetonitrile. and subsequent
separation of the product mixture. The mono-imidazole porphyrin’Z can
_be carried through a variety of reaction sequences to produce blocked
or functionally derivatized porphyrins of varing polarity and steric
bulk (Scheme 3). Although the iron complexes of most of these com-
pounds did not form isolable oxygen adducts at room temperature,
kinetic studies have shown that local polar groups assume a principal
role in determining CO and 02 binding, Table 2 and 3. Detailed
discussion and analysis of these results have been published
elsewhere.8

The separation of functionalized porphyrins from by-products was
tedious. In general, large excesses of reagents were required to
prevent cross-coupling and polymerization. Two methods were generally

employed for crude purification before final separation on preparative

TLC plates or columns, both utilizing the difference in basicity

10.

 

nucloophilo

 

 

Scheme 3.

 

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11.

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.ocmaaou :He

 

 

 

 

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u: 8.... H .H . ~oxa x L. cesoaeou

 

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12.

 

 

 

 

 

 

 

 

 

 

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13.

between the desired porphyrin and by-products. The first method
involved extraction of the porphyrins into 80% phosphoric acid,
several washings with methylene chloride, and subsequent neutraliza-
tion and extraction. The second method, generally giving a higher
recovery, involved chromatographic separation of the protonated
species. Reaction mixtures were protonated with acetic acid and then
washed through a column of silica gel. The by-products were eluted
with methylene chloride-acetic acid, followed by the desired porphyrin
which was freed with triethylamine.

Thermal Atropisomerization

 

The isolation of atropisomers in tetraphenyl porphyrins 13' 2" 7

and now diphenyl porphyrins is evidence for the restricted rotation of
phenyl rings. To allow ring rotation, the porphyrin skeleton must
undergo severe deformations to minimize steric constraints between
o-substituents and pyrrole protons or ring methyl groups. The energy
barrier for this rotation by thermal and photochemical processes in
TPP systems has been the subject of an investigation.

The activation energies for thermal rotation in the o-diamino and
o-diacetamido DPE have been obtained. The kinetic studies were
carried out by monitoring the rate of isomerization using thin layer
chromatography and UV-vis spectroscopy at several different ‘
temperatures. Table 4 lists the temperatures, rates, and AG+ calcu-

lated for the acetamido, amino, and related TPP systems.

 

,tl\\

 

14.

Table 4. Rate_Constants and Activation Parameters for the
Thermal Atropisomerism of Daphenyl Porphyrins and
Related Tetraphenyl Porphyrlns.

 

 

Diphenyl Porphyrin T C k. 5 AG
(acetamide)2. cis 115 9.7 x1o'“ 28.2
120 1.9 x10"3 28.0
132 5.5 x10"3 28.1
141 1.5 xlO'2 27.9
(amino)2. cis 87 7.9 x10-” 26.2
98 2.6 x10"3 26.2
109 7.8 x10"3 26.2
112 1.1 x10”2 26.1
123 2.5 x10’2 26.2
Tetraphenyl Eorghxrin
(o-hexadecylamide)uf 81 1.7 x10-“ 27.0
108 u.5 x1o’” 28.3
136 2.2 x10'3 29.2
(o-pivalylamide)4* 108 2.5 x10—5 30.5
138 5.6 x10'” 30.4

* reference 9.

15.

The slower rates for the diamino versus diacetamido DPE are
expected due to the increased size of the substituent which interacts
with the ring methyls during isomerization. The value of 28 Kcal/mol
of the diacetamido is comparable to those of acyl substituted
tetraio-aminophenyl) porphyrins.9 Intuitively, the addition of
flanking methyl groups should bring more hindrance than the B-pyrrole
protons in preventing rotation. However. the absence of an increase
in AH+ for the OPE system suggests that this is not true. This may be
due to the more flexible nature of the diphenyl porphyrin. To
minimize interaction between phenyl rings and beta-substituents during
rotation, the ring skeleton must twist around the methine carbons. In
the diphenyl system, since two phenyl rings are replaced by two
protons at the meso positions, ring distortions may occur easier.
Therefore the added steric constraints introduced by the beta-methyl
groups may be compensated by the greater flexibility of diphenyl
porphyrin.‘
1H NMR of Free Base Porphyrins

 

The 1H NMR spectra of all free base porphyrins, recorded on a 250
MHz instrument, have proven essential in the identification of mono-
and di-substituted porphyrins used in construction of these unique
heme models. As shown in Figure l, the ring methyl groups flanking
the phenyl rings in the OPE derivatives appear uniformly shifted ca. 1
ppm upfield versus etioporphyrin II due to the diamagnetic ring
current of phenyl rings. The peripheral ethyl groups and methine

protons are not affected by the phenyl rings but would be expected to

 

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16.

 

 

 

 

 

 

 

 

 

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Figure 1.

1L-

T—f ff r f

a . 6 4 2 0

Comparative 250 MHz 1H NMR spectra of deriva-
(A) (amino) DPE,

tized di henyl porphyrins: .
trans ( g; (B) (amino).(p-tBu-benzamidg)DPE,
trans ( a (C) (p-tBu-benzamide) DPE, trans ( )3

(D) (p- Bu-benzamide) DPE. cis (£0); (E) (m- m-

CHZ-benzamide)2DPE. t ans (27). fl“

17.

reflect any reduction in porphyrin ring current if large distortions
in the skeleton are present. Since no deviation was observed, we
believe that the OPE derivatives are essentially as flat as other
ordinary porphyrins. The planarity of the system, however, cannot be
used to judge the flexibility of the macrocycle as the system would
assume a planar configuration to maximize delocalization. The ring
methyl groups served as a diagnostic tool in probing the symmetry of
products. Figure 1A, c, 0 illustrate unsubstituted and symmetrically
substituted systems, showing a singlet for the ring methyls. Figure
18, E are typical of assymmetrical substitutions, hence a pair of
singlets for the four methyl groups. The ethyl groups also reflect
symmetry but the patterns are more complex. In the aromatic region,
amide formation causes large downfield shifts of the protons ortho to
the amine, due to deshielding by the carbonyl group. The NH proton of
the amideappears at 86.9ppm for the aliphatic acids and 88ppm for
benzoic'acids, again due to the deshielding by the phenyl-ring held
above.

The aromatic protons of the bis-p-t-butylbenzamide DPElgaand l9,
Figure 1C, D appear as a singlet in the trans isomer but the expected
AA'BB' pattern in the cis isomer. As DMSO-d6 was added portion wise
to a C0613 solution of the cis isomer, Figure 2, the quartet collapsed
into a singlet. The cis isomer is more congested than the trans
isomer and aggregation or solvation serves to prevent free rotation

and equilibration of the aromatic protons of the blocking group.

18.

AK“‘~—-——- 3:7 A38
fl

is
H

i
E

”Mi/fix m

.—..—— ‘

1

L3
~*-*"J \‘-~—_... 7:3

I s
;t\"'\

‘d” ¥~————IOO%:CDC%

for the
' e 2. Effect of solvent on the resonances .
Figur aromatic protons of the blocking group 1n (p:
tBu—benzamide)2DPE, 018 \19). A = CD813. B —
D5280" d6 0

Attachment of imidazoeyl ligands was easily determined by the
appearance of the imidazole protons which usually appeared as three
singlets, Figure 1E. The resonances were shifted upfield relative to

the free ligand, due to coordination to the inner pyrrolic NH protons.

19.

Electronic Spectra

Diphenyl porphyrins exhibit a phyllo-type spectra, bands IV > II>
III> I, characteristic of mono and di-meso substituted porphyrins.
The spectra of the free base porphyrins, Table 5, are nearly
independent of substituent effect due to the insulating effect of the
phenyl rings.

Large effects due to coordination are observed in the spectra of
zinc and iron DPE, Table 6. Coordination of appended imidazole by
zinc results in an overall red shift, c.a. 10 nm, in the electronic
spectrum. Pronounced effects are also observed in the ferric hemes
which can assume several spin states depending upon the coordination
sphere. Systems containing one appended imidazole exhibited a ferric
heme chloride spectra unique to those without coordinating ligands.
The high local concentration of imidazole in appended systems favors
the formation of the monoimidazole hemin chloride complex which would
be impossible to observe in non-appended systems. 'The high local
imidazole concentration was also evidenced in the spectra of his
appended systems, which at room temperature showed the bis coordinated
species. Similar results could not be obtained with non-appended
systems unless the temperature was reduced or a large excess of
extraneous ligand was added, Fig. 3. The addition of acids to the
appended systems generated spectra identical to the non-appended
systems due to protonation of ligands and disruption of coordination.

NMR, Iron DPE

 

The 250 1H NMR of key paramagnetic iron diphenylporphyrins have

20

Table 5. Electronic Spectra Data of Selected Free Base
Diphenyl Porphyrins.

I II III IV Soret

(amino)2 DPE. cis {2)
2H 625(1.9)a 576(6.6) 541(5.6) 507(16.1) 409(186)
Zn 57u(11,2) 539(18.0) 500(2.7) 412(350)
H+ 62u(6.7) 574(12.2) 53u(5.o) u20(220)

(p-tBu-benzamide)2 DPE. trans (3)
2H 625(3.8) 575(8.7) 542(6.9) 508(15-0) 409(180)
Zn 576(13.9) 540(19.u) 502(3.5) u13(3u7)

(p-tBu-benzamide)(m—ImCH2 benzamide)DPE. trans (22)
2H 625(3-0) 575(7-7) 542(7-7) 508(14.8) 410(182)

Zn 582(7.u) 552(2o.1) 424(328)

8+ 624(8.3> 576(1u.2) 535(3 5) 438(223)
(m-ImCH2 benzamide)2 DPE, trans (1})

2H 628(2.7) 575(7.5) 542(7.1) 508(15-5) “10(187)

Zn 586(6.8) 552(2o.6) 509(3.0) u25(358)

H+ 622(8.o) 575(13.5) 537(3.2) “39(210)

(N02)2 DPE, cis and trans
2H 629(2.8) 578(6.7) 5u5(6.1) 509(17.5) h08(175)
H+ 617(6.4) 572(13-7) 535(2.7) 429(290)

(OH)2 DPE. trans (22)
2H 625(2-9) 573(6.8) 541(6.9) 506(15-3) “05(190)

aWavelength in nm; extinction coefficient X 10'“ in

parentheses.

Table 6.
plexes.

(p—tBu—benzamide)2 DPE. transa (EU

FeCl 6h6(4.h) 583(2.9)
FeOH 578(8.2)
FeIm2

(p-tBu-benzamide)2 DPE. cisa (L_)
FeCl 6U3(u.3) 556(2.6)
FeOH 585(5.0)
FeZO 594(5-“)

(1m(CH2)3NHCONH)2. transb (12)
FeIm2

(acetamide)zDPE. transb (12)

FeC1 6u5(o.ou) 586(0.03)
FeOH 575(0-97
(m-ImCH2 benzamide)2 DPEb (Ll)
FeIm2 562(0.0h)
Fe(HCl) 6u3(o.ou) 581(0.03)

(p-tBu—benzamide).(m-lmCH2

FeCl 629(o.o3) 574(o.ou)
Felinz
FeOH 579(0.07)

a H .
wavelength in nm;

benzamide)DPE

extinction coefficients

21.

539(6.9)

534(9-1)

537(7.o)

565(1o.7)

.CE)

527(o.o7)
5h1(0.07)

b()

"I
I
N

539(C.C91

X 16'“

509(9 0) u13(62.8)
u75(13.u) hou(86.1)
“12(11b)
511(9.6) h1u(70.5)
u76(15.6) u05(1o7)
buo(36.2) 397(8u.9)
u08(1.o)
510(o.1o) 386(1.o)
u73(o.16) uoz(1.0)
u12(1.o)
510(0.09) “39(0-36)
508(0.08) u08(1.o)
uc7(1.c)
LE3(0.11) u05(1.c)

in parentheses.

Extinction coefficients relative to soret in parentheses.

Electronic Spectra Data of Selected Iron(IIl) Diphenyl Porphyrin Com-

388(90.3)
362(u3.8)

388(100)
36o(5o.2)
35u(UB.5)

362(0.56)

389(1.o)

22.

 

 

ABSORBANCE

 

 

 

I I
400 560 600 700

Figure 3. Electronic spectra of Fe(III)PCl complex of
(p-tBu-benzamide) DPE, trans (9) (--—-); and
the effect of adding excess imidazole (

 

23.

been recorded, Table 7. The proton HHR of these complexes routinely
span several hundred ppm due to large scale isotropic shifts resulting
from contact and dipolar spin interactions. Spectral assignments are
difficult due to the lack of observable spin-spin splittings,
distortions of peak intensities due to the wide spectral widths
required, as well as the complexity of the systems. Partial
assignments were based on correlation with well characterized FeOEP
and FeTPP systems 10' 11' 12 and variable temperature measurements
which distinguish paramagnetically shifted signals, e.g., as the
temperature is lowered upfield shifted peaks will shift further
upfield and downfield shifted peaks will shift further downfield. The
integrity of the iron compounds was verified by converting them to the
low spin Fe(II)ImCO complexes. These diamagnetic systems appeared to
be less symmetric than the parent free base porphyrins.

Analysis of ambient and variable temperature spectra proved
invaluable in determining the effectiveness of blocking and ligating
groups. The characteristic isotropic shifts and splitting patterns
revealed the spin states (coordination sphere) and oxidation state of
the central metal in these complex systems.

Sterically Protected Heme and Hemin Hydroxide

It is well known that in the presence of OH', ferric hemes
dimerize in solution to yield the Fe(III)20 P-oxo speciesm. which
makes the isolation of hemin hydroxide nearly impossible for most iron
porphyrins. The lJ-oxo dimer is also formed when ferrous hemes

undergo autoxidation. This is the major drawback in the use of simple

24.

Table 7.
Porphyrin Complexee.

.1:9n.212benxl Enxnnxxine

.nnznbxzin , .zinx.£fl, __£flz .Azb. EM
(p-tBu-benzamide)ZDPE. tren- £2)

FO(III)CI -5h -39. -37 ~15 - -9

PO(III1OH -38 -31. -27 ~13 - '5

Fe(11111nz -15.5 -9 - -6

PO(II)IICO 2.01. 2.32 3.8 9.1-6.3
(p-tBu-benzamide)ZDP£. cie (£9)

Fe(III)C1 -5u -39 -16 - -e

PC(III)20 -1.0 -u.2 -8 - 5

(ecetemide)ZDPE. trans (13)
r.(111)c1 -5u -uo. -37. -36 -16 - -e
Pe(111)1m2 -16.h -3-9 '9 ' '5

(ecetamide)ZDP£. cis (1?)

FoiIII)CI -55 -39. -38 -16 - -8
PeiIII)0H -ho -32. -30 -13 - -7
(m—ImCHZ benzamide)2DPE. trans (13)
Pe(IIIlIm2 -26 -5.2 -9 - -5
Pe(II)Im2 2.u 3.9 9 - 6.5
FI‘II)ImC0 Zeke 2e) 3.8 9 - 6e2
(Im(CH2) NHCONH)ZDPE. trans (13)
Fe(III 1m2 -1h.1 -12 - -3
?e(II)ImCO ' 2.39. 2.42 3.8 7.2 - 8.6

(p-tBu-benzamide). (m-ImCszenzemide)DPE. trans (g?)

re(111)c1 -5u -ua. -h1 -1h - -6
. . '39- ’37

FeiIII)Im2 -15.3. -15.1 ~1h - -5
Fe(11)1mCO '2.3. 2.u 3.8 6.3 - 9.1

(p-tBu-benzamide). (1m(CH2)3NHCONH)DPE trans ‘(231

FQ(III)C1 ’5e°50 ’59-0 “fine '530 '13 ' '6
- O. —38
PO(II)1ECO 2.“ 3.8 6.3 - 9.1

(p—tBu-benzamide). (In(CH2)zCONH)DPE. trane (a?)

Pe(III)Cl -5a.o. -56.5 -u3. -38 -9 - -6
(p—tBu-benzoete)ZDPE. trans (£3)

PCCIII)CI -56.1. '55o6 ~02. '37 '15 - -8
(uquCHz benzoete)ZDPE. trane (a?)

PO(III)IDZ -23.1 -6.0 -10 - -6

-6e
-u,

0
O‘CD‘J U‘

|
O\
O\

o.3.o.h '

1.7

-Oe23

 

61

59

“3‘0
(D'fl

9.8

63

65

10.1

60

9.8

60

Obeerved NIH Shift- of Protone in Selected IroniII)/illl) Diphenyl

tBu
1.
0-5.
~2.
0.7.

0 0"3 M

1-5

-o.5

CM CO
3

0.“. 2.1

tBu

1. 2

-2.0
0.7

1-5

1e2

0.19. 0.23

25.

hemes as models for studying 02 binding in the hemoglobin 80d
myoglobin. In the protein, the heme prosthetic group is invariably

immobilized within the polypeptide matrix, therefore, formation of
hemin hydroxide (hematin) is commonplace. In fact, such hydroxide
species may be crucial in the enzymatic functions of catalase,
peroxidase, and cytochrome oxidase.

In order to prevent p-oxo dimer formation in iron popphyrins,
steric blockage must be incorporated to protect both faces of the heme
group. A large number of encumbered heme models aiming at producing
stable o2 complexes have been synthesized, but these compounds are
generally protected only on one face.1'2'3 Only recently have studies
been made on the preparation of doubly protected systems capable of
forming stable hemin hydroxides.14’18 A tetra(5-anthryl) porphinato
ferric hydroxide was mentioned in a communication by Cense and
LeQuan.15 Balch and coworkers synthesized ferric hydroxides of
tetraiz, 4; 6-trimethoxyphenyl)porphyrin and tetramesitylporphyrin via
air oxidation of ferrous hemes or by the metathesis of hemin chlordie
with aqueous sodium hydroxide.14 Formation of hemin hydroxide was
also observed with tetra (2, 4, 6-triphenylphenyl)porphyrin by
Suslick.17 Except for Balch's work, most of these compounds are
difficult to prepare and have not been fully characterized. Our trans
amino-OPE I: if property derivatized should offer a simple alternative
for the preparation of hemin hydroxides.

Both the cis- and trans- bis(p-t-buylbenzamide)-DPE,‘gvand 12,

were converted to the hemin chloride by standard procedures. Exchange

26.

of the anion was carried out either by elution of the halide through
basic alumina or washing a dichloromethane solution with aqueous NaOH.
After completion of the exchange, as evidenced by changes in the
visible spectra, Figure 4, the solutions were dried and evaporated to
dryness. The cis isomer dimerized readily to the thermodynamically
more stable p-oxo dimer as shown by spectral changes, and can be
easily crystallized from methanol-CHZCIZ- The trans hemin hydroxide
did not dimerize upon isolation but crystallization in methanol often
gave mixtures due to the formation of methoxide. Thus, a solid form
of trans hemin hydroxide was simply obtained by lyophilization from
benzene or precipitation from hexane.

Cyclic voltammograms of the cis and trans hemin chlorides, as
expected, are identical. However, the isolated products following
metathesis are unique. As shown in Figure 5, the voltammogram of the
open-face cis isomer is indicative of a lJ-oxo dimer exhibiting
oxidation of both rings in a stepwise fashion. The voltammogram of
the trans product indicates the 51/2 for the Fe(III)/Fe(II) couple is
about 500 mV more negative in the hydroxide than in the chloride. The
greater difficulty in reduction can be accounted for by the higher
electron density of the central metal, due to the electron donating
ability of the hydroxide ligand.

Infrared spectroscopy provided unambiguous evidence of the
presence of an OH group in the trans product, Figure 6. The hydroxide
exhibits a sharp peak at 3615 cm’l, which is absent in either the

trans chloride or cis (i-oxo dimer. Previous investigators have used

ABSORBANCE

Figure 4.

 

27.

 

 

I ' I v j , T
400 500 600 700 nm
Electronic spectra of Fe(III) complexes of

(p— tBu- benzamide) DPE, cis (10 i Fe(III)PCl
(nu); Fe( (III)Por~°l (---—) ; Fe III)P20 (—).

28.

 

 

1 l I 1 I 1
1.0 005 o -005 - I 00 - 1.5

Volte ve. SCE

Figure 5. Cyclic voltammograms of Fe(III) complexes of
(p-tBu-benzamide) DPE (a) cis. Fe(III)P O;
(b) trans, re(111i PCl: (c) trans. Fe(IiI)P0H
filthe presence of CO (----).,

29.

 

 

 

 

 

 

 

 

 

Figure 6. Infrared spectra of Fe(III) complexes of (p-
tBu-benzamide) DPE in CCl . (a) solvent; (b)
trans. Fe(III)2PCl; (c) tians. Fe(III)POHp°
(d) cis, Fe(III)P20.

30.

the presence of this peak for the formation of hemin hydroxides.16'

18’19 Balch and co-workers, however, did not observe this peak in any
of their systems, only a broad band centered at 3400 cm'1 which can be
attributed to occluded water.14

The 1H HHR of the cis lJ-oxo dimer, Figure 7, is indicative of a
strongly antiferromagnetically coupled species: there are no
resonances beyond 810 ppm. (For paramagnetic species, we conform to
the convention that downfield shifts from THS take the negative sign.)
The trans hydroxide shows large isotropic shifts for the ring methyl
groups and the CH2 protons centered at 8-38 and ~30 ppm, respectively.
The features of this spectrum are similar to the high spin ferric
hemin chloride: there are large isotropic shifts and splitting of CH2
and t-butyl peaks. The isotropic shifts of the trans hydroxide also
exhibit a near Curie behavior with linear dependence on reciprocal of
temperature, Figure 8. The curvature of the Curie plot can be

accounted for by the dipolar contribution“:20 to the isotropic shift:

H/H

2
O - CCODIT + cdip/T

where ccon A/h (359/(12K/21) 12K/2

C

dip 239232 (3cosze-1) D/9k2r3

The calculated value of D is 10.0 cm'l, very similar to that measured

for the tetramesitylporphyrin Fe-OH.14

3L

 

 

 

 

 

 

Fe-CI
Fe-OH L
Fe-CI‘ i k
0
13 F
.20
1 l T ‘ - l I '1 fl l fr
‘60 -40 '20 0

Figure 7. Comparative 1H NMR spectra of paramagnetic
Fe(III) complexes of DPE 2 8: l3.

32.

 

 

 

 

Figure 8. Curie plot for the Fe(III)POH
phenyl porphyrin g2.

 

complex of di-

lapirepic SM"

(pen)

33.

The observed change in the isotropic shifts between hemin chloride
and hydroxide for our trans bisip-t-butylbenzamideloPE’2 is 15 ppm,
which is quite large in comparison with the ca. 1 ppm difference
observed for the tetramesitylporphyrin system.14 In principle, the
isotropic shifts are extremely sensitive to spin density variations
caused by ligand or conformational changes. Large changes in
isotropic shifts have been observed in ferric hydroxides of flexible
porphodimethenes.2l The sensitivity of the shifts ofci—methylenes
units in 5,15-dimethyl octaethylporphodimethene were attributed to the
folding of the ring skeleton, resulting in reduced transfer of spin
density from the metal to the ring. The flexibility of the
diphenylporphyrin system has already been alluded by the ease of
atropisomerization. It is possible that the large changes in
isotropic shift may be related to the intrinsic flexibility of the OPE
ring.

Gunter and Mander6 have observed a solvent dependent equilibrium
between hemin chloride and hydroxide in octamethyl diphenylporphyrins.
He have observed a similar equilibrium with unhindered DPE, e.g.,
cis-bis(acetamide)-DPE 14, however, no equilibrium was observed for
the doubly protected DPE systems. Further evidence for this
equilibrium was observed in bis-imidazole formation. Cense and Le
Quan and Felton used ligand exchange reactions as evidence for
hydroxide formation.15'18 The ferric hydroxide should undergo
metathesis while the strongly coupled ,J-oxo dimers should be

resistant. Both the P-oxo dimers and ferric hydroxides of DPE undergo

34.
reactions with extraneous imidaZole, Figure 9, but at different rates.

The slower exchange rate observed for the p-oxo dimer indicates

conversion to the hydroxide may precede ligand exchange, Equation 3.

Fe(III)P20 + ”20;: 2 Fe(III)POH =___1L 2 Fe(III)PIm2 (3)

Hemes Appended with Imidazole Ligands

 

The presence and importance of the proximal histidyl imidazole in
hemoglobin and myoglobin oxygen binding has been well established by
studies on the natural systems as well as models. The histidyl ligand
is also present in other heme proteins such as cytochromes c, b5.
cytochrome oxidase. and peroxidases. Therefore, it is not surprising
that imidazole-iron porphyrin have been and continue to be a crucial
model in biomimetic studies of heme-containing systems. However, the
use of free imidazoles and simple hemes to generate S-coordinate
complexes is not possible due to the competing reaction to form
6-coordinate hemochromes. In compounds that are sterically protected
on one face of the porphyrin ring, i.e., capped, crowned hemesZI'22
and cofacial diporphyrins, a bulky imidazole can be used effectively
to prevent bis-coordination. In other less shielded systems,
including our trans-(p-t-butylbenzamide) DPE derivatives, this
approach is unsatisfactory. An alternative to generating S-coordinate
heme without the use of external ligand is to covalently attach an
imidazole to the heme group. This tactic originally reported by

Harme and Hager23 and later successfully employed by Chang and

ABSORBANCE

 

35.

 

 

 

Figure

 

9e

Electronic spectra of Fe(III) complexes of
(p-tBu-benzamide)DPE, (a) trans. Fe(III)POH
----); and the effect of adding excess imida-
zole ( ). (b) cis. Fe(III)P 0(--—-): and
the effect of adding excess N- e imidazole

 

 

36.

Traylor4 to allow equilibrium and kinetic studies of 02 binding to a
variety of myoglobin models.7'24'25 The main advantage of strapped
bases is the generation of a high local concentration of ligand near
the metal center. In addition, perturbations affecting the imidazole
coordination can be easily introduced by modifying the sidechain or
spacer group connecting the base and the ring. This arrangement also
more closely resembles the natural system where the interaction
between heme iron and histidine is subject to protein conformational
controlsl Indeed, studies by Traylor and coworkers have shown that
strain introduced by chain length or substitution has a dramatic
effect on the electronic, spectroscopic, and chemical properties of
heme models.24

Alkyl chain-linked imidazole can be easily added to the OPE system
using two routes, Scheme 2. The trans mono-t-butylbenzamido-mono-
amino-DPE‘E’was coupled with N-imidazolyl alkanoic acid chlorides of
varying length. Alternatively, porphyrin’é’was reacted with phosgene
to generate the carbamoyl chloride which when combined with amino
appendages produced the urea linked system in excellent yields. The
structure of these imidazole-appended DPE's were characterized by NMR,
IR, and elemental analysis, 1H NMR spectra of the diamagnetic zinc
complexes of these compounds provided additional support for the
purported structure. Zinc porphyrins prepared by heating the
porphyrin with a saturated methanolic solution of zinc acetate in
methylene chloride, bind imidazole strongly. Thus, coordination of

the intramolecularly linked base resulted in the upfield shift of

37.

imidazole protons and protons of the alkyl strap which are held
rigidly over the ring. Conversely, the addition of trifluoroacetic
acid resulted in protonation of imidazole and disruption of
coordination, thereby, causing downfield shift for the methylene
protons as the side chain moved away from the porphyrin.

Our previous experience as well as the experiments described below
suggest that an alkyl chain strapped imidazole is still able to form
both inter- and intra-molecular complexes. In an effort to construct
a more restricted system, porphyrin £2 (also’Z and 33-44) was designed
(Scheme 2, 3). The m-benzyl linkage is less floppy and has fewer
degrees of freedom of rotation than alkyl straps7. Synthetically, the
imidazole m-toluic acid chloride was difficult to obtain because of
the insolubility of the acid. A two-step method was therefore devised
as described in the Synthesis section. The advantage of the benzyl
linked imidazole is illustrated by the following 1H NMR experiments
using ferric hemes.

At room temperature, mixing a 2:1 stoichiometric ratio of
l-methylimidazole and the trans-diacetamido-DPE Fe(III)C1 gave a
spectrum, Figure 10, typical of high-spin (s=S/2, d5)species, which
shows that 2 equivalents of external base are not sufficient to form
appreciable amounts of 6-coordinate hemichrome. The equlibrium, of
course, can be shifted to the bis-imidazole complex (s=1/2) by
addition of excess base or lowering the temperature. As temperature
was reduced, the spin equilibrium became obvious. Complete conversion

to the 6-coordinate low spin complex was prevented by solubility

.naoo CH odoumcwefi ahcposia mpcoam>wsdo N
wcficfimpcoo Away mama» .meNonaEmpmomv mo Noaasoo
HomAHHvam mo manomam mzz :H «coccmnoc muspmmoQEma .oH mm=Mwm

40.

limitations. The higher local concentration of imidazole in strapped
imidazoles is seen in the spectrum of the bis urea linked imidazole
heme, Figure 111 At room temperature, only the low-spin species was
observed. However, the appearance of ring methyl groups as broad
bands as well as the splitting of the alpha CH2 PPOtONS when
temperature was lowered suggests that mixtures of inter- and

intro-molecularly bounds species exist in solution, Equation 4.

 

 

.. In)
2 I'm 2 Im Fla
, ' .
Fe + Re T—_— I'm I'm ( ’4)
I I
In Im fie
Inl

The bis-benzylimidazole heme exhibited a different type of
behavior, Figure 12. A relatively sharp resonance at.S-26 ppm
corresponding to the ring methyl protons was observed. Also as the
temperature was reduced, the ring methyl and alpha CH2 VGSOPGHCES
remained as sharp singlets, reflecting a high degree of symmetry in

the bis-imidazole complex. There was no indication of exchange.

4L

MAMA}! I

 

 

 

wfiwb

...‘BL/kJ'WL/j )ltithMLi/rli .

’15 ~10 . -5 6 5

 

 

Figure 11. Temperature dependent 1H NMR spectra of the
Fe(III)PIm2Cl complex of (Im(CH2)3NCOHNH)2
DPE, trans (12) in CD013.

42.

.maooo Ca Ammv mCMHp .mmDNAmcwEmNcmnmzoEHlEv ho

 

 

 

 

 

 

meQEoo HUNEHmAHHHme 0:9 Mo mupommm msz zH PsouCommU mmzpmuomsoe .N. omzwflm
o 0... ON... on:
FFL L L|L|L L L - L L . i L L L . L L p L L L . L L L
J); /\ ( i 1 room
i: i<i - ...

 

 

 

 

 

 

 

 

43.

The large downfield shift of the ring methyl groups, observed at 8
-26 ppm in the bis-benzylimidazole system is noteworthy. The ring
methyl resonances of bis-imidazole complexes of model hemes, e.g.,
etioheme, occur aroundTS-IG ppm. As well, extrapolation of the shifts
for non-covalently linked N-methylimidazole diphenyl heme system gives
a signal around 8-17 ppm at room temperature; and for free
N-benzylimidazole plus diacetamido-DPE hemin chloride, the peak is
estimated at -16 ppm.

To determine the influence of the appended benzylimidazole , a
mixed species consisting of trans-(p-t-butylbenzamido), (imidazolyl-
toluamido)-DPE Fe(III)C1, £7, and imidazole was prepared. The
presence of the appended benzylimidazole to create a high local
concentration facilitated coordination of the second (free) imidazole
to form a bis adduct with only a small excess of ligand. The ring
methyl protons appeared as a pair of singlets in this system
indicating assymmetric coordination, Figure 13. Interestingly the
shift was normal; 8-15.1 ppm and -15.3 ppm at room temperature. The
ester analogue of the bis benzylimidazole appended system shows the
ring methyl protons at 5-23 ppm.

These results concur with previous observation524'25'28 that the
spin density distribution at the peripheral substituents of ferric
hemes are very sensitive to axial ligand orientation or ring distor-
tion. The covalently bound bis-benzylimidazole either introduced
distortion to the ring or more likely, assumed a coordination geometry

at variance with the free ligand. In the mixed complex, the shift is

.oaoumuwsfl mpcmam>flsuo m..:pa3 mauMo Cw mama» .mmnaouwemNCmn
.onflEmNCopismpinv mo xoamsoo Ho

mxoeHie.
eHm..HH.ea me» me saueuean mzz m. .m. enema.

n+ 0 mi 0.: Mai

44.

 

 

 

 

 

 

 

45.

normal because whatever distortion brought about by the internal
ligand is compensated for by the external ligand. In the ester
analogue of the bis-benzylimidazole appended systems, the shifts are
closer to the free systems because of the greater flexibility of the
ester linkage, allowing a more favorable geometry or less distortion.
fi:Ketoamide Appendaggg

In our effort to construct orientation specific groups appended to
the hemes, we also explored the use of p-ketoamide groups as linkage
units. p-Carbonyl groups may form hydrogen bonds to the amides,
thereby, directing the attached functional groups over the porphyrin
ring. The malonyl amide porphyrins (gé-gzl were synthesized by first
treating the mono-imidazolyl toluamide DPE’ZJwith an excess of malonyl
dichloride, followed by the appropriate amine.

The ability of the p-ketoamide linkage in directing groups over
the porphyrin core was indicated by 1H NMR spectra. The malonyl
derivatives displayed an upfield shift for the terminal N-alkyl
groups. For example, the t-butyl protons appear as a singlet at 1.3‘
ppm in t-butylacetamide, but at 0.6 ppm in the malonyl porphyrin.

Kinetic studies of C0 binding to the malonamide hemes were
performed to detect distal steric effects brought about by these more
”peptide-like“ blocking groups. However, little differences were
found in the CO association rate as the amide varied from primary,
secondary, to tertiary.29 It has been shown previously that the C0
association rates are sensitive to the steric crowdedness at the heme

iron.3-22'30 The lack of change in this rate would reflect on the

46.

fact that the H-alkyl substituents need not be coplanar with the amide
carbonyl and that they can assume conformations which have a minimum
interaction with the incoming ligand. It thus may be difficult to
control or predict the distal steric effect of malonamide appendages.
Phenolic and Ester linked Diphenyl Porphyrins

The ease in synthesis and versatility of the amino DPE led to the
study of analogous systems. Phenolic and ester linked porphyrins,
although less directed than the corresponding anilides, would serve as
excellent models in studying orientational effects and distal polarity
on C0 and 02 binding.

Initial attempts to generate these species with
o-methoxybenzaldehyde led to excellent yields of the slightly soluble
porphyrinogen and porphyrin. The low solubility of the products helps
to drive the porphyrinogen formation to completion. Unfortunately,
attempts to deprotect the phenols failed due to the low solubility of
the methoxy porphyrins.

Salicylaldehyde was also found to react rapidly and the parent
phenolic porphyrins were much more soluble. The reaction was carried
out at O‘C to increase selectivity and zinc acetate was introduced to
promote a template effect. The yields of the porphyrin isolated after
oxidation were routinely > 40%. The high polarity of the cis
atropisomer 21 versus the trans form fig allowed an easy separation on
silica gel. The individual isomers reacted under the same conditions
as the analogous anilides to yield sterically encumbered and imidazole

appended systems, 24 and 25.
N N

47.

Summary and Further Studies

The improved synthesis and utilization of hybrid diphenyl
porphyrins was demonstrated. The increased rigidity due to ring alkyl
groups allowed the construction of blocked and chelated iron
porphyrins of fixed geometry. The effectiveness of the p-t-butyl-
benzamide blocking group was demonstrated by the formation and
characterization of ferric hydroxides. Chelated systems, incorporat-
ing a variety of appendages, provided a high local concentration of
imidazole favoring formation of S-coordinate intermediates useful for
the heme-ligand binding studies.

Kinetic studies on systems having minor changes in the blocking
group revealed the importance of local and distal polarity on oxygen
association and dissociation rates. The importance of H-bonding in
the stabilization of the heme-oxygen complex and steric factors in C0
binding were also implied. 8a,8b

Further studies would involve the clarification of polarity
effects by utilizing blocking groups which cannot hinder coordination
of ligands. The phenolic porphyrins can also be used in studying
distal polarity effects and the possible role of the amide NH in
stabilization of complexes. Reduced porphyrin derivatives can also be
constructed by saturation of peripheral double bonds using standard
techniques, e.g., diimide reduction yields the cis and trans diamino
chlorins, 48; These systems can be derivatized in the same fashion as
the porphyrins to reveal the influence of ring saturation. The

presence of octa-alkyl substituents may also allow oxidation to the

ba
Al
ch
dl
ab

de

it
im‘
So]

at],

48.

versatile geminal ketones,58 although steric congestion may be
prohibitive.

Experimental
1

 

H NHR spectra were recorded on a Bruker NM-ZSO MHz instrument.
Absorption spectra were measured using a Cary 219 Spectrophotometer.
IR spectra was obtained in KBr wafers on a Perkin Elmer 237B

spectrometer. Elemental analysis were performed by Spang; C, H, N,
analyses were within $0.423. Methylene chloride was distilled from

CaHZ and THF was distilled from LiAlH4 before use.

Thermal Atropisomerization

 

To ortho-xylene (50 ml) heated to constant temperatures in an oil
bath was added the cis DPE (20 mg) in methylene chloride (5 ml).
Aliquots were analyzed at intervals by TLC (silica gel, methylene
chloride/hexane). The separated isomers were placed in a cuvette,
diluted to a constant volume with 10% MeOH/CHZCl2 and relative
absorbance determined at 403 nm. The rates of isomerization were
determined by least squares plots.

1H NMR

 

Free base and iron porphyrin were measured in CDCI3 (ca. 0,01 m)
at zo'c, Fe(III)P(Im)2 was prepared by addition of two equivalents of
imidazole in CDC13. Fe(II)P(Im)C0 was prepared by mixing a CDC13
solution of the iron porphyrin with aqueous sodium dithionite under C0
atmosphere.

Fe Insertion

 

Porphyrin (20 mg) was dissolved in 1:1 THF:benzene (20 mL).

Wt

.Yl

Ga

49.

containing collidine (2 drops) and FeBrz (40 mg). The solution was

heated under argon for ca. 30 min and the solvent was removed in
vacuo. The residue was redissolved in CHZCIZ. extracted with 10% "Cl.
washed with water and eluted on alumina column. To obtain the ferric
chloride form, the solution was washed with saturated NaCl in 0.1N
HCI. The hydroxide was obtained by washing a CH2c12 solution with 10;
NaOH. Alternatively the hemin chloride was eluted through a basic
column of alumina until the absorption spectra indicated complete
ligand exchange.

4,4'-Diethyl-3,3'-dimethyl-2,2'-dipyrrylmethane
5,5'-Bis(ethoxycarbonyl)-4,4'-Diethyl-3,3'-dimethyl-2,2'-dipyrryl
Lmethane (13) gm, 0.4 ml, which was obtained easily from ethyl
4-ethyl-3,5-dimethyl-pyrrole-2-carboxylate, was dissolved in hot
ethanol (952, 400 ml). To this solution after it was heated to a
gentle reflux with stirring, a solution of NaOH (50 gm/IOO ml water)
was added carefully through the condenser. Refluxing was_continued
for 2 h, after which the condenser was removed and the volume was
reduced to 1/3. The mixture was diluted with water (100 ml) and then
brought to vigorous refluxing for 6 h without interruption. At the
end of this period, a layer of brown oil was separated. The mixture
was allowed to cool to room temperature, the solidified material was
filtered off, washed with water until neutral, and dried (quantitative
yield). The freshly prepared decarboxylated dipyrrylmethane has a
light tan color and a characteristic chared bone smell; it slowly

darkens in the air but can be stored indefinitely in a refrigerator.

50.

1H van (coc13) 51.12(t, 6", He). 2.03(s, 6H, Me), 2.47(q,4H, CH2).
3.79(s. 2H. CH2), 6.35(m, 2H, H). 7.26(br s, 2H, NH). m.p. 49-50'C.
Mass Spectrum (70 eV), 230 (m+). calc. 230.
5,15-Bis(o-nitrophenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylpor-
m

4,4'-Diethyl-3,3'-dimethyl-2,2'-dipyrrylmethane (6 g, 26.1 mmol)
and o-nitrobenzaldehyde (3.9 g, 26.1 mmol) was dissolved in methanol
(300 ml). After the solution was deaerated by bubbling with argon for
10 min, p-toluene-sulfonic acid (1.4 g, 7.4 mmol) was added. The
mixture was stirred for 15 min, then allowed to stand in the dark at
room temperature. The crude yellow porphyrinogen began precipitating
within 1 h. After 6 h at room temperature, the solution was cooled
and kept at 4°C overnight. The solid was collected and washed with
cold methanol.

The crude porphyrinogen 3’(2.5 g) was dissolved in tetrahydrofuran
(200 ml) and treated with a solution of o-chloranil (2.5 g) in THF (20
ml). The solution was stirred at room temperature for 30 min. The
porphyrin which precipitated out during this period was too finely
divided to be filtered. Thus, the solvent was evaporated and the
protonated residue was redissolved in methylene chloride. A solution
of methanol-triethylamine (4:1) was added to reprecipitate the
porphyrin. The product was collected by filtration and wash washed
with cold methanol and THF (yield: 2.29); 1H NMR (CDC13-TFA) 8-1.84(br

s, 4H, NH), 1.37(t, 12H, Me), 2.29(s, 12H, Me), 3.74(q. 8H, CH2).
8.13(m, 4H, ArH), 8.48(m, 4H, ArH), 1.22(s, 2H, mesa); uv-vrs

law

(‘5

IE
aq
ml
ev
m
an.
pOl
wil
eve

col

51.

(dichloromethane) max (EmH) 629 nm (2.5), 578 (6.3), 545 (5.8), 509
(15.0). 408 (150).

Porphyrinogen, 1H NHR (coc13) 81.15(m, 12H, He), 2.27(s, 12H, He).
2.41(q, 8H, CH2), 4.21(s, 4H, meso cuzl. 4.71(br s, 4H, NH). 8.73ibr
s, 8H Ar).
5,15-Di(o-aminophenyl)-2,8,12,18-tetraethyl-3,7,13,l7-tetramethylporph-
yglgg_(l). (2)

To a solution of the nitrophenylporphyrin 4'(4 g, 5.5 mnol)
dissolved in 12 N HCI (180 ml) was added stannous chloride dihydrate
(9.4 g, 41.3 mmol). The mixture was stirred at room temperature for
16 h. The solution was diluted with water (100 ml), neutralized with
aqueous ammonia (75 ml) and extracted with methylene chloride (3 x 100
ml). The combined organic layers were washed with water, dried, and
evaporated to dryness. The crude porphyrin was redissolved in a
minimum amount of CHZCIZ. acidified with trifluoroacetic acid (1 ml)
and irradiated under a sun lamp for 2 h to recover any over-reduced
porphyrin. At the end of this treatment, the solution was diluted
With CHZCIZ, washed with water and saturated NaHC03, and then
evaporated to dryness. The crude product was purified on a silica
column (6 x 30 cm) using 21 methanol- CH2c12, The trans isomer was
eluted first, followed sluggishly by the cis isomer. Yields from a 2
g crude mixture: trans, 0.74 g (372) and cis, 1.1 g (551).

Cis-isomer (2) m.p. > 380'C; 1H NMR (c0c13) 8-2.43(br s, 2H. pyrrole
NH). l.79(t, 12H, Et). 2.70(S, 12H, Me). 3.63 (5, 4H, MHZ), 4,04(q,

 

8H, Et), 7.1(d, 2H, Ar), 7.19(t, 2H, Ar), 7.60(t, 2H, Ar), 7.67(d, 2H,
Ar), 10.25(s, 2H, meso).

ml

PY

wl'

SE

Na?

pu1

m. ......

chl

dis:

solu

ml)

52.

Trans-isomer (1) m.p. > 380'C; 1h NHR (coc13) 8-2.44(s. 2H. pyrrole
NH), 1.79(t, 12H, Et), 2.70(s, 12H, Me). 3.67 (s, 4H, NHZ), 4.05(q,

 

8H, Et). 7.10(d,'2H Ar), 7.17(t, 2H, Ar). 7.57-7.65(m, 4H, Ar).
1023(s, 2N, meso).
Trans 5,IS-di(o-acetamido)-2,8,12,18-tetraethyl-3,7,13,17-tetramethyl
porphyrin (13)

Excess acetyl chloride (1 ml, 11 mmol) was added to a CH2c12 (100
ml) solution of trans diamino DPE (100 mg, 0.15 mmol), followed by
pyridine (1 ml, 12 mmol). The mixture was stirred for 0.5 h, diluted
with water and stirred for l h further. The organic layer was
separated and washed successively with; 10% HCI, H20, sat. aqueous
NaHC03. and then dried and evaporated to dryness. The product was
purified on silica gel to yield the acetylated product, (105 mg, 952);
m.p. 365°C; 1H NMR (coc13) 8-2.42(s, 2H, NH), 1.30(s, 6H, Me), 1.77(t,
12H, He). 2.54(s, 12H, Me), 4.05(q, 8H, CH2), 5,92(5, 2H, NH), 7.51(t,
2H Ar). 7.83im, 4H, Ar), 8.80(d, 2H, Ar), 1030(5, 2H, meso).
Trans-S,15-bis(o-(p-t-butylbenzamidolphenyl)-2,8,12,18-tetraethyl-3,7,

 

13,17-tetramethylporphyrin (2)

A mixture of p-t-butylbenzoic acid (2 g, 11.2 mmol) and thionyl
chloride (2 ml) in chloroform (20 ml) was refluxed under nitrogen for
3 h. The solution was evaporated to dryness to yield a yellow oil.

A portion of the crude acid chloride (89 mg, 0.45 mmol) was
dissolved in methylene chloride (10 ml) and added dropwise to a

solution of bis-amino porphyrin 1’(300 mg, 0.45 mmol) in CHZCIZ (100
ml) containing triethylamine (1 ml, 7.17 mmol). After completion of

tr
lid

‘2

NH.
Ar]
2H
C a

53.

the addition, the mixture was refluxed for 2 h under nitrogen before

poured into water (100 ml). The organic layer was separated, washed

successively 52 HCI (150 ml), with saturated NaHC03 solution (150 ml).

and H20 (150 ml). After drying over sodium sulfate, the mixture was

evaporated to dryness and separated on a series of preparative silica
gel TLC plates (Analtech 1500 micron) using CH2c12, and acidic alumina
columns.

The first band, containing trans-bis(o-(p-t—butylbenzamido)phenyl)
porphyrin 2 was collected and crystallized from CHZCIZ‘MGOH to yield
purple crystals (80 mg, 18:); IR: co: 1670 cm'l; 1H NHR (00013) 5
-2.33(br s, 2H, pyrrole NH). 0.73(s, 18H, t-butyl), 1.75(t, 12H, Et).
2.60 (s. 12H. CH3), 4.05(q, 12H, Et), 6.42(s, 8H, Ar), 7.55(t, 2H,
Ar), 7.82-7.96(m, 4H, Ar). 7.99(s, 2H, NH), 9.10(d, 2H, Ar). 11.32(s,
2H, meso); Anal. Calcd. for €55H72N402 c 80.78, H 7.40, N 8.75; Found
C 80.63, H 7.31, N 8.42.

The second band, which is the major one, corresponds to
trans-S-(o-aminophenyl)-15-(o-(p-t-butylbenzamido)phenyl) porphyrin 5:
was also crystallized from CH2c12-MeoH (135 mg, 502); 1H NMR (CDC13) 5
-2.40(br s, 2H, pyrrole NH), 0.70 (s, 9H, t-butyl), 1.72(t, 6H, Et),
I.76(t, 6H, Et), 2.57 (s, 6H, CH3), 2.70(s, 6H, CH3), 3.68(s, 2H,
NHZ). 4.05(m, 8H, Et), 6.47(s, 4H, Ar), 7.10(d, 1H, Ar), 7.l7(t, 2H,
Ar), 7.5-7.95(m, 6H, Ar), 8.05(s, 1H, NH), 9.10(d, 2H, Ar), 10.26(s,
2H, meso); Anal. Calcd. for C55H60N60 C 30.45. H 7.35. N 10.24; F0004
C 80.22, H 7.27, N 10.16.

The third band was the recovered starting material,

I—i

[:9

HI
ac
at
et
ch
an.
ch‘
cli
CH

)8]

aci

an.
addi
PFOg
comp

SeDa

m).

' 54.

trans-5,IS-bis(o-aminophenyl) Parphyrin I, (92 mg, 312).
Trans-S-(o-(p-t-butylbenzamido)phenyl)-15-(o-(m-N-imidazolyl)-
tyoluamido)phenyl)-2,8,12,IB-tetraethyl-3,7,13,17-tetramethyl-
pgrphyrin (£1)

m-Toluic acid (10 g, 73.5 mmol) dissolved in nitrobenzene (60 ml)
was heated to 125'C. The solution was illuminated with a sun lamp
while bromine (11.74 g, 73.5 mmol) was added dropwise. After the
addition was complete, (ca. 2 h) the solution was stirred 6 h further
at 125'C. The solution was then cooled and poured into petroleum
ether (100 ml). The solid was collected and recrystallized from
chloroform; m.p. 145-‘46‘6. oL-Bromo-m-toluic acid (1.5 g, 6.98 mmol)
and an excess of thionyl chloride (2 ml, 27.4 mmol) in methylene

chloride (20 ml) was refluxed under N2, After the solution had

cleared and evolution of gas ceased (ca. 30 min), the excess SOCIzand

CHZCIZ were removed in vacuo to yield the crude acid chloride as a

yellow solid.

A mixture of porphyrin 5 (40 mg, 0.0486 mmol) andci-bromo-m-toluic

acid chloride (45 mg, 0.193 mmol) in cuzc12 (60 ml) was refluxed under
N2 for 2 h. The volume of the mixture was reduced to about 20 ml and

an excess of sodium imidazolate (90 mg, 1 mmol) in CH3CN. (20 ml) was

added all at once. The mixture was heated to refluxing and the
progress of reaction was monitored by TLC. After the reaction was

complete, the solution was diluted with water. The organic layer was

separated and successively extracted with 5% HCI (100 ml), H20 (100
ml). saturated NdHCO3(100 ml), H20 (100 ml), dried over Na2804 and

ll
((1

me

'55.

evaporated to dryness. The product was purified through a silica gel
pad (3 x 15 cm) eluted with 5: HeOH/CHZClZ.

Recrystallization from hexane-CHZCIZ. yielded purple flakes. 41.5
mg (842). 1H NMR (C0C13) S-Z.3I(s, 2H, pyrrole NH). 0.73(s, 9H,
t-butyl), 1.74(M, 2H ArCHZ). 4.00(m, 8H, Et), 5.18(S, 1H, IM-H).
5.22(S, 1H, Im-H), 6.25-6.6(m, 8", Ar), 7.25-8.1(m, 8H, ArNH), 8.96(d.
1H, Ar), 9.08(d, 1H, Ar), 01.29(s, 2H, meso). Anal. Calcd. for
C55H68N802 c 78.85, H 6.82, N 11.15; Found c 78.59, H 6.78, n 10.96.
Trans-S-(o-(p-t-butylbenzamido)phenyl)-15-(o-(m-bromotoluamido )-
phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetra-methylporphyrin (29)

A mixture of porphyrin 5J(40 mg, 0.049 mmol) and bromo-m-toluic
acid chloride (45 mg, 0.193 mmol) ln CHZCIZ (60 ml) was refluxed under
"2 for 2h. The mixture was diluted with water, the organic layer
separated, and washed with sat. aqueous NaHC03. dried and evaporated
to dryness. The crude residue was purified on silica columns, eluted
with 100: CH2012.

Recrystallization from CHZCIZ-methanol yielded purple solid, 37 mg
(742) 1H NMR (coc13) 80.76(s, 9H, t-butyl), 1.73(t, 12H, Me), 2.58(s,
6H, Me), 2.60(s, 6H, Me), 4.0(m, 8H, CH2), 4,43(s, 2H, ArCHZ), 5,23(d,
1H, Ar), 6.47(s, 4H, Ar), 6.74(t, 1H, Ar), 7.40(t, 1H, Ar), 7.45-8.05
(m, 8H, Ar, NH), 9.02(d, 1H, ArH), 9.08(d, 1H, Ar). 10.31(s, 2H,

meso).

mg

V0

mg

re

H8

(2
(2(

la}

00

The

32
CH2

CH3:

1H,

Ar)

iii,

C55H.

56.

Trans-S-(o-aminophenyl)-15-(o-(m—(-N-imidazolyl)toluamido)phenyl)-2,
8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (Z)

<K-Bromo-m-toluic acid chloride (70.8 mg, 0.304 mmol) was added to
a methylene chloride (200 ml) solution of the diamino porphyrin 1’(200
mg, 304 mmol). The green solution was refluxed under Hz for 3 h. The
volume was reduced to 1/3 and a solution of sodium imidazolate (500
mg, 55 mmol) in acetonitrile (100 ml) is added. The mixture is

refluxed for 2 h. further before evaporated to dryness. The residue

was redissolved 1" CHZCIZ (150 ml), extracted successively with water
(2 x 200 ml), 51 HCl (200 ml), H20 (200 ml), saturated with NaHC03
(200 ml). and H20 (200 ml). After drying over Na2504, the organic

layer was evaporated to dryness. The reaction mixture was separated
on silica gel columns (4 x 30 cm). The least polar band corresponding
to the starting material (64 mg, 322) was eluted with 1001 CHZCIZ-

The second band which contains the desired porphyrin was eluted with
3x HeOH/CHZCIZ- The product was further crystallized from hexane-
012012 to give purple flakes (122 mg, 482); 1H NMR (CHZCIZ) 6-2.32(br
s, 2H, pyyrole NH), 1.72(m, 12H, Et). 2.60(s, 6H, CH3),2.70(s, 6H.
CH3), 3.22(s, 2H, ArCHZ), 3.68(s, 2H, NHZ), 4.02(q, 8H, Et), 5.18(s,
1H, Im-H), 5.64(s, 1H, IM-H), 6.25-6.33(m, 5H, Ar, Im-H), 7.10(d, 1H,
Ar), 7.19(t, 1H, Ar), 7.5-7.7(m, 4H, Ar, NH), 7.93(t, 1H, Ar), 8.10(d,
1H, Ar), 8.96(d, 1H Ar), 10.25(s, 2H, meso). Anal. Calcd. for

c55H58N80 C 78.17, H 6.68, N 13.26; Found C 78.24, H 6.80, N 13.07.

an

NHL

57.

Trans-5-15-bis(o-(m-(-N-imidazoyl)toluamido)phenyl)-2,8,12,18-
tetraethyl-3,7,I3,17-tetramethylporphyrin (1})
In the above synthesis, the last band eluted with 101 HeOH/CHZCl2

was bis-imidazole porphyrin 11. It was recrystallized from

hexane-Cflzm2 to afford purple flakes (37 mg, 12:); 1H NMR (CDC13) s
-2.32(s, 2H, pyrrole NH), 1.73(t, 12H, Et), 2.58(s, 12H, CH3). 3.33(s.
4H. ArCHZ), 4.00(q,8H,Et), 5.16(s,2H,IH-H), 5.78(s, 2H, IM-H). 6.30(d.
2H, Ar). 6.40(t, 2H, Ar), 6.52(d, 2H, Ar). 6.60(s, 2H, Ar). 7.57(s,
2H, NH). 7.64(t, 2H Ar), 7.93(t, 2H, Ar), 8.05(d, 2H, Ar), 8.96(d, 2H,
Ar), 9.29(s, 2H, meso); Anal. Calcd. for C56H75N1002; C75.12. H 7.35.
N 13.45; Found C 76.05, H 7.21, N13.47.
Cis-S-(o-aminophenyl)-15-(o-(m-«X-N-imidazolyl)toluamido)
phenyl)-2,8,12,18-tetrathyl-3,7,13,17-tetramethylporphyrin (8)

This mono-imidazole appended porphyrin was prepared in a manner
analogous to the trans isomer using the cis diamino porphyrin 2; 1H
NMR (60613) 8-2.32(s, 2H, pyrrole-NH), 1.75(m, 12H, Et), 2.60(s, 6H,
CH3), 2.97(s, 2H, ArCHZ), 3.53(m, 2H, NHZ). 4.03(Q. 8H, Et). 4.55(s.
1H, IM-H), 5.33(s, 1H, Im-H), 5.77(s, 1H, IM-H), 6.13(s, 1H, Ar),

6.24(d, 1H, Ar), 6.43(t, 1H, Ar), 6.70(d, 1H, Ar), 7.10(d, 1H, Ar),
7.17(t, 1H, Ar), 7.5-7.7(m, 4H, Ar), 7.92(t, 1H, Ar), 8.14(d, 1H, Ar).
8.93(d, 1H, Ar), 19.27(s, 2H, meso).
Cis-S,15-bis(o-(m-(«EN-imidazoly)toluamido)phenyl)-2,8,12,18-
tetraethy1-3,7,13,17-tetramethylporphyrin (12)

This compound was resulted accompanying the preparation of the cis

mono-imidazole porphyrin, analogous to the trans system; 1H NMR

“I?

p-

CH;
Arj
Ar}
Cis

tel

rea
2.5
NH
1H
1H

Q

m

COnt

58.

(CHZCIZ) 8-2.31(br s, pyrrole NH). l.7l(t, 12H, Et). 2.57(s, 12H,
CH3), 3.53(s, 4H, ArCHz). 3.97(m, 8H, Et). 5.08(s, 2H, lN-H). 5.50(s,
2H, IH-H), 5.84(s, 2H, IM-H), 5.92(s, 2H, Ar), 6.35(d, 2H, Ar).
6.45(t, 2H, Ar). 6.73(d, 2H, Ar). 7.62(t, 2H, Ar). 7.92(t, 2H, Ar).
8.09(d. 2H, Ar). 8.32(s, 2H, NH), 8.90(d, 2H, Ar).
Cis-S,15-bis(o-(m-(oL-bromotoluamido))phenyl-2,8,12,18-tetraethyl-
3,7,13,17-tetramethylporphyrin

 

This porphyrin was made in an analogous fashion as the mono
p-t-butylbenzamido porphyrin 23. 1H NHR (CDC13) 8-2.32(s, 2H, NH).
1.77(t, 12H, Me), 2.62(s, 12H, He). 3.02(s, 4H, ArCHz), 4,oa(q, 8H,
CH2). 6.22(s, 2H, Ar), 6.46(t, 2H, Ar), 6.61(d, 2H, Ar), 6.70(d, 2H,
Ar). 7.63(t, 2H, Ar). 7.83(s, 2H, NH). 7.95(m, 4H, Ar), 9.03(d, 2H,
Ar), 10.32(s, 2H, meso).
Cis-S-(o-aminOphenyl)-15-(o-(m-(ctrbromotoluamido))phenyl)-2,8,12,18-

 

tetraethyl—3,7,13,l7-tetramethylporphyrin (6)

Thisci-bromotoluyl porphyrin was isolated from the previous
reaction mixture 1H NMR (CDC13) 8-2.40(s, 2H, NH), 1.75(m, 12H, Me),
2.58(S, 6H, Me). 2.70(s, 6H, Me). 2.94(s, 2H, ArCHz). 3.66(S, 2H.
MHZ), 4.07(m, 8H, CH2), 6.10(s, 1H, ArH), 6.4-6.8(m, 3H, Ar), 7.09(d,
1H, Ar), 7.18(t, 1H, Ar), 7.5-7.7(m, 4H, Ar), 7.76(S, 1H,NH), 7.90(t,
1H, Ar), 8.01(d, 1H, Ar), 9.00(d, 1H, Ar), 10.27(s, 2H, meso).
Trans-5-(o-acetamidophenyl)-15-o-(m(64-N-imidazolyl)toluamido)
phenyl-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (43)

To a solution of porphyrin’1’(40 mg, 0.047 mmol) in CH2Cl (40 ml)

containing pyridine (1 ml, 12.4 mmol) was added an excess of acetyl

U\
9
m

59.V

chloride (0.5 ml, 7 mmol). After stirring 1 h at room temperature,

water (100 ml) was added and the mixture stirred 1 h further. The

organic layer was separated and washed with 102 HCI, H20. sat. aqueous
NaHC03, dried and evaporated to dryness. The crude product was
purified on a silica gel column (21 HeOH/CHZCI) dfld recrystallized
from hexane-Chzm2 to yield purple-black crystals (34 mg, 33:). 1H
NMR (CDC13)<S'2.33($, 2H, NH). 1.31(s, 3H, Hec0). 1.78(t, 12H,Me).
2.52(s, 6H, Me), 2.58(s, 6H, He), 3.33(s, 2H, ArCHZ), 4.02(m, 8H,
CH2), 5.16(s, 1H, Im-H), 5.78(s, 1H, Im-H), 6.20(s, 1H, Im-H).
6.25-6.55(m, 3H, Ar). 6.60(s, 1H, Ar). 6.87(s, 1H, NH), 7.5-8.1(m, 7H,
Ar, NH). 8.79(d, 1H, Ar), 8.96(d, 1H, Ar), 10.30(s, 2H, meso).
Cis-S-(o-acetamidophenyl)-15-o-(m-(oL-N-imidazolyl)toluamido)
phenyl)‘2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (43)

The cis isomer was made in the same fashion as the trans form
except starting with the cis imidazole appended aminoporphyrin 8: 1H
NMR (60613) 8-2.52(s, 2H, NH), 1.38(s, 3H, MeCO), 1.75(m, 12H, Me),
2.50(s, 6H, Me), 2.60(s, 6H, Me), 3.90(s, 2H, ArCHZ), 4.00(m, 8H,
CH2), 6.28(d, 1H, Ar). 6.56(s, 1H, NH). 7.10(5, 1H, Im-H). 7.30(s, 1H,
Im-H), 7.42(t, 1H, Ar), 7.51(d, 1H, Ar), 7.55(s, 1H, Im-H), 7.64(t,
1H, Ar), 7.8-8.1(m, 4H, Ar). 8.23(d, 1H, Ar), 8.60(m, 2H, NH, Ar).
8.97(d, 1H, Ar), 10.25(s, 2H, mesa).
Trans-S-(o-(m-(ci-N-imidazolyl)toluamido)phenyl)-15-(o-(3,5-bis
(ethoxycarbopyl)benzamido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetra

methylporphyrin (33)

 

A solution of prophyrin Z (40 ml, 0.0474 mmol) and pyridine (0.5

ml
we
mg
ad

mi:
su<
10C
oil
The

pro

The
HCl
Cry:
582)

cruq
EXtr.
”ate:
with
Se”Lur
gel b

metho

60.

ml, 6.18 mmol) in methylene chloride (20 ml) was added dropwise to a
well-stirred solution of 1,3,5-benzenetricarboxylic acid chloride (500
mg, 1.88 mmol) in methylene chloride (40 ml). After completion of the
addition (ca. 30 min), the mixture was stirred at room temperature for
1 h. Ethanol (5 ml) was added and the reaction refluxed for 3 h. The

mixture was poured into water, the organic layer separated and washed

successively 10: HCl (2 x 100 ml), H20 (100 ml), NaHCO3 (sat aqueous.
100 ml). H20, and then dried over Na2504. After evaporation to a red

oil, the product was purified on a silical gel column, (2 x 25 cm).
The benzene triester was eluted first with 2% HOAc-CHzc12, The
protonated porphyrin was washed off the column with 52 Et3N-CHZCIZ-
The porphyrin containing fraction was extracted successively with 5%
HCl, H20, NaHC03, dried over Na2504 and evaporated to dryness.

Crystallization from hexane-CH2c12 yielded purp1e granules (30 mg,
582).

An alternative purification method involved extraction of the
crude reaction mixture into 801 phosphoric acid. The acid layer was-
extracted several times with methylene chloride, then diluted with
water and neutralized. The neutralized su5pension was back extracted
With CHZCIZ and the organic phase was washed with 5% HCl, then H20,
saturated aqueous NaHCO3- The yield after chromatography on silica
gel by this extraction method were generally lower than the first

method.

61.

IR: Jcomo, 1720 curl; 1H mm (coc13) 8-2.30(br s, pyrrole-NH),
0.38(t, 9H, OEt), 1.73(m, 12H, Et), 2.58 (s, 12H, CH3), 3,23(s, 2H,
ArCHz), 3.37(q,'4u, ocnzcwal. 4.00(m, an, Et), 5.03(s, 1H. IH-H).
5.71(s, 1H, Im-H),6.11(s, 1H, Im-H). 6.23-6.72(m, 4H, Ar), 7.4-8.1(m,
11H, Ar, NH), 8.97(m, 2H, Ar), 10.28(s, 2H, meso); Anal. Calcd. for

c53H80N805C 73.88, H 7.30, N 10.14; Found C 74.02, H 7.43, N 10.10
Trans-5(o-(m-(CirN-imidazolyl)toluamido)phenyl)-15-(o-(3,5-bis

(n-butolycarbonyl)benzamido)phenyl)‘2'8'12'la'tetraethy1'3'7'13'17'tet
ramethylporphyrin (23)

 

This porphyrin was prepared by the above procedure except ethanol
was replaced by n-butanol; yield from’ZE 63:. 1H NMR (coc13)16=2.4(br
s, 2H, NH). 0.50(t, 6H. Me), 0.77(m, 8H, CH2), 1.73(m, 12H, Me),
2.60(s, 12H, Me), 3.04(s, 2H, CH2), 3.34(t, 4H, ocnzl. 4.03(m. 8H.
CH2), 5.06(s, 1H, IM-H), 5.67(s, 1H, IM-H), 6.16(s, 1H, IM-H).
6.2-6.6(m, 8H, Ar), 7.46(d, 2H, Ar), 7.5-8.1(m, 6H, Ar, NH), 8.95(d,
2H, Ar), 10.27(s, 2H, meso)
Trans-5-(o-(m-(OL-N-imidazolyl)toluamido)phenyl)-15-(o-(3,5-bis
(hydroxymethyl)benzamido)phenyl)2,8,12,18-tetraethyl-3,7,13,17-tetrame

 

thylporphyrin (88)

 

Porphyrin 83 (20 mg, 0.18 mmol) was dissolved in freshly distilled
tetrahydrofuran (25 ml). Excess lithium aluminum hydride in THF was
added and the reaction stirred for 3 min at room temperature. The
reaction was carefully diluted with water (50 ml), followed by CHZCIZ
(30 ml). The organic layer was separated and washed with water,

brine, and dried over Na2504- After evaporation, the mixture was

3,5

wit

OVEI
Chrc
yiel
Bu-c
3.23
In),
6.56
meso;

74.2;

62.

separated on thick layer silica gel plates, the 51 MeOH-CHZCIZ- The
major band was collected and lypholized from benzene to yield a red
powder (13.3 mg, 70:; IR: 0c01670 cm‘1,)0H 3400 cm ‘1; In nun (c0013)8
-2.4 (br s, 2H, pyrrole NH). 1.75(m, 12H, Et), 2.55(s, 6H, CH3),
2.59(s, 6H, CH3), 3.16(s, 4H, ArCHZ), 3.25(s, 2H, ArCHZ). 3.98(m, 8H.
Et). 5.13(s, 1H, Im-H), S.69(s, 1H, Im-H), S.92(s, 2H, Ar), 6.1-6.6(m.
6H, Ar), 7.4-8.1(m, 8H, Ar), 8.91(m, 2H, Ar). 10.27(s, 2H, mesa).
Trans-5-(o-(m-(CL-N-imidazolyl)toluamido)phenyl)-15-(o-(3,5-bis
(n-butylaminocarbonyl)benzamido)phenyl)-2,8,12,18-tetraethyl-3,7,l3,l7
-tetramethylporphyrin (as)

This compound was prepared by procedures analogous to that of
3,5-diethyl ester porphyrin 83; The crude diacid chloride was treated
with excess n-butylamine and the resultant mixture was refluxed
overnight under N2. After purification by extraction and column
chromatography, the amide was crystallized from hexane CH2c12; 40:
yield. 1H NMR (coc13) 8-2.4(br s, 2H, pyrrole-NH), 0.48(t, 6H,
BU‘CH3), 0.75(m, 8H, Bu-CHZCIZ), 1.73(m, 12H, Me), 2.58(s, 12H, Me).
3.23(s, 2H, benzyl), 3.34(t, 4H, CHZO), 4.01(m, 8H, CH2), 5.06(s, 1H.
1m), 5.66(s, 1H, 1m), 6.15(s, 1H, Im), 6.28(d, 1H, H), 6.40(t, 1H, H),
6.56(m, 2H, H), 7.4-8.1(m, 11H, Ar, NH), 8.95(m, 2H, Ar), 10.26(s, 2H,
meso); Anal. Calcd. for 653880N806 c 74.58, H 7.82, N 12.08; Found c
74.21, H 7.93, N 11.82.

63.

Trans-5-(o-(m¥(oL-N-imidazolyl)toluamido)phenyl)-15-(o«(3,5-bis
(N,N-diethylaminocarbonyl)benzamido)phenyl)-2,8,12,18-tetraethyl-3,7,1
3,17-tetramethylporphyrin (88)

 

This was prepared as described for the diester porphyrin 83;
Excess diethyl amine was added to the diacid chloride-porphyrin.

After refluxing overnight under N2 the product was purified as

described; yield: 47:. 1H NMR (00013) 8-2.38(or s, 2H. pyrrole NH).
-0.83(br. 6H. NHC20H3), 0.19(br, 6H, NCHZCH3), l.42(br, 4H, NCHZ).
1.74(m, 12H, Et). 2.24(br, 4H, NCHZ), 2.56(s, 6H, CH3), 2.61(s. 6H.
CH3), 3.28(s, 2H, ArCHZ), 4.00(m, 8H, Et), 5.10(s, 1H, IM-H), S.73(s,
1H, Im-H), 6.18(s, 1H, IH-H). 6.23-6.6(m, 6H, Ar). 6.68(s, 1H, Ar),
7.5-8.1(m, 8H, Ar, NH), 8.97(m, 2H, Ar), 10.28(s, 2H, meso).
Trans-5-(o-(m—(cL-N-imidazolyl)toluamido)phenyl)-15-(o-(3,5-bis
(N,N-di-ipropylaminocarbonyl)benzamido)phenyl)-2,8,12,18-tetraethyl-3,
7,13,17-tetramethylporphyrin (33)

 

This compound was prepared by procedures identical to that for the
diethyl analogue 88 except that isopropylamine was used to quench the
acid chloride; yield: 55:. 1H NMR (C0013)i8-2.4(br s, 2H,
pyrrole-NH), 1.28(d, 12H, i-Pr), 1.72(t, 12H, Me), 2.56(s, 6H, Me),
2.60(s, 6H, Me), 3.22(s, 2H, benzyl), 4.00(m, 8H, CH2), 4.27(m, 2H,
i-Pr), 5.04(s, 1H, Im), 5.65(s, 1H, 1m), 6.14(s, 1H, 1m), phenyl:
6.30(d, 1H), 6.40(t, 1H), 6.47(s, 2H), 6.54(d 1H). 6.58(s, 1H).
6.68(s, 1H), 7.3-8.2(m, 8H, H, NH), 8.96(d, 1H), 9.03(d, 1H), 10.26(s,

2H, meso).

.Hi.

h:

be

9X

"6

50‘

SU(

Naz

Dad

64.

Trans-5-(o-(m-Qggfl-imidazolyl)toluamido)phenyl)-15(o-(3,5-bis

(butylthiocarbonyl)benzamido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-

 

tetramethylporphyrin (21)

This compouond was prepared by procedures identical to that for
the ester and analogues 83, 8; except butanethiol was used to quench
the acid chloride. After recrystallization from hexane-CH2c12. yield
71:. 1N NMR (coc13).842.07(br s, 2H, NH), 0.57(t, 6H, Me), 0.78(m,
4H. CH2). 1.75(m, 20H, He, CH2). 2.58(s, 6H, Me), 2.60(s, 6H, He).
3.10(s, 1H, IM-H), 4.00(m, 8H, CH2). 4.97(s, 1H. Im-H), 5.50(s, 1H,
Im-H), 6.15(s, 1H, IM-H), 6.2-6.6(m, 3H, Ar), 7.16(d, 2H, Ar), 7.38(s,
1H, Ar), 7.65(m, 2H, Ar), 7.7-8.0(m, 4H, Ar, NH), 8.11(d, 1H, Ar),
8.94(d, 1H, Ar), 9.01(d, 1H, Ar). 8.94(d, 1H, Ar), 9.01(d, 1H, Ar).
10.28(s, 2H, meso).
Trans-5,15-bis(o-(3-(N-imidazolyl)propylureido)phenyl)-2,8,12,18-

tetraethyl-3,7,13,17-tetramethylporphyrin (11)

 

To a solution of porphyrin 1 (20 mg, 0.03 mmol) in tetrahydrofuran
(30 ml) containing pyridine (1 ml) was added an excess of phosgene in
benzene (1 ml, 21 1 mmol/ml). After stirring for 20 min at room
temperature, the excess phosgene was removed in vacuo. A solution of
excess 3-(N-imidazolyl)propylamine22(0.5 ml, 517 mmol) in THF (20 ml)
was added and the mixture stirred overnight. After removal of
solvents, the resultant oil was redisolved in CHZCIZ» "35094
SUCCES$1V61Y With 52 "Cl. H20, NaHCO3 (sat. aqueous) and dried over
Na2504- The crude product was dried and purified through a silica

pad. crystallized from MeOH-CH2012 to yield a purple solid (19.2 mg,

bi

9H

m .fl

om~

met

Aft

org

Sat

DOr

Hem

2.4:

Im~i

7,84

65.

80:). 1H NMR (00013) 81.34(t, 4H, CH2). 1.75(t. 12H. Me). 2.61(s.
12H. Me). 3.19(n. 4H. CH2, 4.00(q. 8H, CH2), 6.30(s, 2H, Im-H).
7.43(c, 2H, Ar); 7.82(m, 4H, Ar), 8.57(d, 2H, Ar). 10.31(s, 2H, meso).

Trans-S-(o-(p-t-butylbenzamido)phenyl)-15-(o-(3-(N-imidazolyl)propylur-

 

eido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (31)
This compound was made in procedures analogous to the
bis-imidazolyl propylureido complex except starting with the
mono-blocked porphyrin g; 1H NMR (CDC13)(5-0.67(m, 2H. CH2). 0.72(S.
9H, t-butyl). 1.70(t, 12H, Et). 1.98(m, 2H, CH2), 2.17(m, 2H, cuz),
2.Sl(s, 6H, CH3). 2.57(s, 6H, CH3). 3.96(q. 8H, Et). 4.38(t, 1H, NH).
5.03(s, 1H, Im-H), 5.32(s, 1H, Im-H). 5.38(s, 1H, Im-H). 6.28(s, 1H,
NH), 6.44(s, 4H, Ar), 7.36-7.94(m, 7H, Ar, NH). 8.57(d, 1H, Ar).
9.08(d, 1H, Ar), 10.22(s, 2H, meso).
Trans-bis-S,15-(0-(3-(N-imidazolyl)propylamido)phenyl)2,8,12,18-
tetraethyl-3,7,13,17-tetramethylporphyrin (1g)

 

This compound was prepared by an analogous procedure as porphyrin
£5 The 3-(N-imidazolyl)propionic acid chloride was added to a
methylene chloride solution of porphyrin 6 containing triethylamine.

After refluxing for 2 h, the mixture was poured into ice water. The

organic layer was separated, washed successively with 5% H01, H20.
saturated aqueous NdHC03, and then evaporated to dryness. The crude
porphyrin was purified on preparative TLC plates (silica gel, 5%
MeOH-CH2012). 1H NMR (00013).So.84(m, 4H, CH2). 1.73(t, 12H, He).

2.45(s, 12H, Me), 3.73(c, 4H, CH2), 4.02(m, 8H, CH2). 6.23(s. 2H.
Im-H), 6.60(s, 2H, Im-H), 6.93(m, 4H, NH, Im-H), 7.52(t, 2H, Ar),

7.84(t, 4H, Ar), 8.70(d, 2H, Ar), 10.27(s, 2H, meso).

66.

Trans-5(o-(p-t-butylbenzamido)phenyl)-15-(o-(3-(N-imidazolyl)
pggpylamido)phenyl)-2,8,12,18-tetraethyl-
3,7,13,17-tetramethylporphyrin(§g)
This compound was prepared in procedures analogous to the blocked

imidazolyl-butylamido complex 89, except utilizing the corresponding

propyl derivative. 1H NMR (60613).80.72(s, 9H, t-butyl), 1.73(m, 14H,
Et). 2.46(s, 6H, CH3). 2.58(5, 6H, CH3). 3.75(t, 2H, CH2). 4.02(m, 8H.
Et), 6.25(s, 1H, Im-H), 6.48(s, 4H, Ar), 6.63(s, 1H, Im-H). 6.85(s,
1H, NH), 7.01(s, 1H, Im-H). 7.56(q. 2H, Ar), 7.90(m, 4H, Ar), 8.0(5,
1H, NH), 8.71(d, 1H, Ar). 9.08(d, 1H, Ar), 10.29(S, 2H, mesa).
Trans-bis-§,15-(0-(4-brom0butylamido)phenyl)-2,8,12,18-tetraethy}e

 

~3,7,13,17-tetramethylporphyrin (18)

 

This compound was made in procedures analogous to the
alkyl-appended imidazole porphyrins 1g, 19. The 4-bromobutyric acid
was the result of hydrobromic acid hydrolysis of butyrolactone.31

Treatment with thionyl chloride produced the acid chloride which was

used without further purification. 1H NMR (CDC13) 8‘2-42(5. 2”. NH).
1.46(t. 4H. CH2), 1.60(m, 4H, CH2), 1.81(t, 12H, Me), 2.54(s, 12H,
Me). 2.86(t, 4H, CH2). 4.05(q, 8H, CH2). 6.88(s, 2H, NH). 7.53(t, 2H.
Ar), 7.87(m, 4H, Ar). 8.76(d, 2H, Ar), 10.30(s, 2H, mesa).
Trans-bis-S,15(o-(N-butyrolactam)phenyl)-2,8,12,18-tetraeth l-

 

3,7,13,l7-tetramethy1porphyrin (22)

 

The preceding bromobutylamido porphyrin 18 was treated with excess
sodium imidazolate in refluxing dimethylformamide. Chromatography on

silica gel revealed a single nonpolar product. 1H NMR (00013) 5

tr

pr
75

ch)
mal
mix
was
The

eXtr

with

67.

-2.40(s, 2H, NH), 0.70(q, 4H, CH2), 1.67(t, 4H, 0H2). 1.74(t. 12H.
Me). 2.20(t. 4H. Chz), 2.60(s, 12H, He), 4.02(m, 8H, CH2), 7.71(m, 2H,
Ar), 7.80(d, 4H, Ar). 8.17(d, 2H, Ar). 10.23(s, 2H, meso).
Trans-S-(o-(p-t-butylbenzamido)phehyl)-15-(o-(m-(OL-acetylthio)
toluamido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin
(fig)

This compound was prepared in procedures analogous to the
N-imidazolyl toluamide, except the bromotoluamido porphyrin as was

treated with an excess of sodium thioacetic acetate. The crude

product was separated on silica gel columns (22 MeOH/CHZCIZ). 31614
755- 1H NMR (60013) 80.78(s, 9H, t-butyl), 1.76(t, 6H He). 2.35(s,
3H, CH3CO), 2.59(s, 6H, Me), 2.61(s, 6H, Me), 4.23(s, 2H, ArCHZ).
6.2-6.7(m, 4H, Ar). 6.48(s, 4H, Ar), 7.5-8.0(m, 8H, Ar, NH), 9.03(d,
1H, Ar). 9.08(d, 1H, Ar). 10.29(s, 2H, meso).
Trans-S-(o-(mr(drN-imidazolyl)toluamido)phenyl)-15-(o-(aminocarbonyl-
acetamido)?henyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethyl-
porphyrin (fié)

A solution of porphyrin’Z’(50 mg, 0.059 mmol) in methylene
chloride (30 ml) under Hz was added to a well stirred solution of
malonyl dichloride (0.5 ml, 5.7 mmol) in CH2c12 (100 ml) and the
mixture was refluxed for 2 h. At room temperature, anhydrous ammonia
was bubbled through the green solution until the color changed to red.
The mixture was then diluted with water (100 ml), separated, and
extracted into 802 phosphoric acid (30 ml). The acid layer was washed

with CH2012 (3 x 100 ml), diluted with water, then neutralized with

ar

ge

go

a 1

NH.

CH:

1H.

7.8

7.9

Tra'

(t-l

tetl

Afte

adde

1.7)

3.21

IH-H

1H,

{N (l

u H
mw no
.d

68.

10: NaOH, and back extracted repeatedly with CHZCIZ (3 x 30 ml). The

combined organic phase was washed with water (100 ml), brine (100 ml).
and evaporated to dryness. The crude product was purified on silica
gel plates. using 21 MeOH-CH2012. The second band, the major band,
gave the desired porphyrin which was lyophilized from benzene to yield
a brown powder (11 mg, 202). 1H NMR (00013) S-3.2(br s, 2H, pyrrole
NH). -0.4S(br s, 2H, NHZ). 1.5(t, 6H, Et). 1.62(t, 6H,Et), 2.17(s, 6H,
CH3), 2.58(s, 6H, CH3), 3.27(s, 2H, ArCH3), 3.6-4.0(m, 8H, Et). 5.0(s,
1H, Im-H). 5.65(s, 1H, IM-H), 6.05(s, 1H, Im-H), 6.20(s. 2H, CH2).
6.50(S. 1H, Ar), 7.3(m, 2H, Ar, NH), 7.6(d, 1H, Ar), 7.70(t, 1H, Ar),
7.80(t, 1H, Ar), 7.96(t, 1H, Ar). 7.40(d, 1H, Ar), 7.64(d, 1H, Ar).
7.94(m, 2H, Ar, NH). 10.0(5, 2H, meso).
Trans-5-(o-(m-(oL-N-imidazolyl)toluamido)phenyl-15-(o-
(t-butylaminocarbonylacetamido)phenyl)-2,8,12,lB-tetraethyl-3,7,13,17-

 

tetramethylporphyrin (43)
This porphyrin was made in an analogue fashion as porphyrin 45.

After addition of malonyl dichloride, an excess of t-butylamine was

added. 1H NMR (00013).S;2.3(br s, pyrrole NH), 0.60(s, 9H, t-butyl).
1.7)t, 12H, Et), 2.34(s, 2H, CH2). 2.50(s, 6H, CH3). 2.60(s, 6H, CH3).
3.21(s. 2H. ArCHz), 4.00(m, 8H, Et), 5.11(s, 1H, Im-H). 5.66(s, 1H,
IHJH), 6.0-6.6(m, 6H, Ar, Im-H, NH), 7.3-8.0(m, 8H, Ar, NH). 8.72(d,
1H, NH). 8.95(d, 1H, Ar). 10.27 (s, 2H, meso).
trans-5-(o-(m-(oL-n-imidazolyl)toluamido)phenyl)-15-(o-(dimethylamino-
acetamido)phehyl)-2,8,12,18-tetraethyl-3,7,13,17-tetamethyl-

porphyrin (41)

69.

This porphyrin was made in an analogous fashion as porphyrin 4g;

1" NMR (C0313)5-.2.35.(br s. pyrrole NH). 1.00(s, 3H, NCH3), 1.70(t,

12H, Et). 2.08(S, 3H, NCH3). 2.52(s, 6H, CH3). 2.59(s, 6H, CH3).
2.73(s. 2H. COCHZ). 3.18(s, 2H, ArCH3). 4.00(m, 8H, Et). 5.14(s, 1H,
Im-H), 5.63(s, 1H, Im-H), 6.2-6.6(m, 5H, Ar, Im-H). 7.5-8.0(m, 6H, Ar,
NH), 8.2(d, 1H, Ar). 8.7(m, 2H, Ar, NH). 8.96(d, 1H, Ar), 10.27(s, 2H,
meso). '
Trans-bis-S,15-(0-(m-(0L-triethylchloroammonium)toluamido)phenyl)-
2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (21)

A mixture of porphyrin 1’(40 mg, 0.060 mmol) and excess bromo-m-
toluic acid chloride (30 mg, 12.8 mmol) in methylene chloride (40 ml)
was refluxed under N2 for 90 min. The mixture was evaporated to
dryness and redisolved in acetonitrile (30 ml). Excess triethylamine
(3 ml, 32.1 mmol) was added to the green solution and the reaction was
stirred at room temperature for 2 h before the mixture was evaporated
to dryness. The residue was redissolved in CHZCIZ (30 Ml). washed
filth H20 (30 ml) and brine (30 ml), and then purified on silica gel
plates (10: MeOH-CHZCIZ). The porphyrin collected from the most polar
band was crystallized from CHZCIZ-hexane to yield a purple brown
power. 1H NMR (C0013)81.48(s, 18H, Me3N). 1.76(t, 12H, Me). 2.62(s.
12“. Me). 3.22(s, 4H, ArCHZ), 4.05(q, 8H, CH2), 5.36(s, 6H, Ar).
5.97(s, 2H, Ar). 6.51(s, 2H, Ar). 7.08(m, 2H, NH). 7.73(t, 2H, Ar).
8.00(t, 2H, Ar). 8.04(d, 2H, Ar), 8.86(d, 2H Ar). 10.37(S, 2H, meso).

mak
dml'.
(CD(
2.5}
CH2)
3H
3H,

9.00

70.

Trans-5-(o-(m—(ct-N-imidazolyl)toluamido)pheny1)-15-(o-(m(ggf-

atrimethylchloroammonium)toluamido)phenyl)-2,8,12,186tetraethyl-

 

3,7,1,17-tetramethylporphyrin (41)
This compound was made in procedures analogous to the bis

quatenary amines except utilizing the mono imidazole appended

porphyrin 1: Yield after recrystallization from CHZCIZ‘hexafle» 71%-
1" "MR (CDCI3) 8-2.50(br s, 1H, pyrrole NH), -2.37(br s, 1H, pyrrole
NH), 0.07(S, 9H, N(CH3)3). 1.75(m, 12H, Et). 2.42(S, 2H, ArCHz).
2.58(5. 6H. CH3), 2.63(s, 6H, CH3), 3.55(s, 2H, ArCHz). 4.04(m, 8H,
Et), 4.32(s, 1H, Ar), 5.21(s, 1H, Im-H). 5.98(S, 1H, Im-M), 6.15(s,
1H, Im-H), 6.39(s, 3H, Ar), 6.63(s, 1H, Ar), 6.90(t, 1H, Ar). 7.16(d,
1H, Ar), 7.4(m, 2H,-Ar), 7.7(m, 2H, Ar), 7.94(m, 2H, Ar). 8.12(d, 1H,
Ar), 8.86(d, 1H, Ar). 8.97(d, 1H, Ar), 10.34(s, 2H, meso).

Trans-5-(o-(m-(ci-N-imidazolyl)toluamido)phenyl)-15-(o-(m-(qgr

 

dimethylamino)toluamido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-

 

tetraméthylporphyrin (40)

This compound was made in procedures analogous to those used in
making the appended quatenary amine 41 except an excess of dimethyl
amine was used in the reaction with aiirbromo intermediate. 1H NMR
(00013).50.98(s, 6H, MezN). 1.74(m, 12H, Me), 2.00(s, 2H, ArCHz).
2.57(s, 6H, Me). 2.61(s, SH, Me), 3.30(s, 2H, ArCHz), 4,01(m, 8H,
CH2). 5.17(s, 1H, Im-H), 5.74(s, 1H, Im-H), 6.23(s, 1H, Im-H). 6.43(m,
3H, Ar), 6.55(d, 1H, Ar), 6.62(s, 1H, Ar). 6.72(d, 1H, Ar). 7.50(m,
3H, Ar). 7.7S(s, 1H, NH), 7.94(m, 3H, Ar, NH), 8.09(d, 1H, Ar).
9.00(m, 2H, Ar). 10.30(s, 2H, meso).

wit
fol
was
per.

”Elf

71.

Transf5(o-(m-(cL-N-imidazolyl)toluamido)phenyl)-15-(o-(m-k&rtrieth¥)’

 

 

chloroammohium)toluamido(phenyl)-2,8,12,18-tetraethyl-3,7,13,17-
tetramethylporphyrin (4g) '

This compound was made in procedures analogous to those used to
make the triethyl ammonium analogue 41, except that triethyl amine was
used in the reaction with the bromo intermediate. 1H NMR (00013) .8
-2.40(s, 2H, NH), -0.52(t, 3H, He). 1.13(q,4H, CH2). 1.30(t. 6H. He).
1.65(t, 3H, Me). 1.74(t, 3H, Me). 2.53(s, 6H, "8). 2.58(5, 6H, Me),
3.00(s, 2H, ArCHZIm). 3.27(q, 4H, CH2). 4.00(m, 8H, CH2). 4.38(s. 1H.
Im-H). 4.66(s. 2H. ArCHzN). 5.13(s, 1H, Im-H), 5.50(s, 1H, Ar),
5.88*s, 1H, Im-H). 6.17(d, 1H, Ar). 6.26(m, 2H, Ar), 6.58(d, 1H, Ar),
6.27(t, 1H, Ar). 7.02(d, 1H, Ar). 7.14(d, 1H, Ar), 7.37(t, 1H, Ar).
7.6-8.l(m, 8H, Ar), 8.86(d, 1H, Ar), 8.97(d, 1H, Ar), 10.27(s, 2H,
meso).
5,15-8is(o-hydroxphenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethyl-

porphyrins (22) (23)

 

4,4'~0iethyl-3,3'-dimethyl-2,2'-dipyrrylmethane (6 gm, 26.1 mmol)
and salicylaldehyde (3.2 gm, 26.1 mmol) were dissolved in methanol
(300 ml). The solution was cooled to 0’0 and deaerated by bubbling
with argon for 10 min. Zinc acetate (1 ml sat. MeOH) was added
followed by p-toluenesulfonic acid (1.4 gm, 7.4 mmol). The reaction
was stirred for 4 h, the solvent was removed in vacuo. The crude
porphyrinogen was dissolved in THF (40 ml) and treated with an equal
weight of o-chloranil. After stirring for 1 h the solvent was removed

in vacuo and the crude solid redissolved in CH2“2 and precipitated

a t
L e\
T t

and

4H

5.1(

72.

with methanol-triethyl amine. The porphyrin was collected by filtra-
tion ahd washed with cold methanol. The isomers were purified and
separated on silica columns, trans isomer elutes with 1002 CHZCIZ. the
cis isomer requires 10% methanol. Yield after recrystallization from
CH2c12-methanol, 3.6 gm, 39%.

trans isomer (£3) 1” NMR (C0513)¢$-2.45(s, 2H, NH), 1.78(t, 12H, Me),
2.64(s, 12H, Me). 3.34(d, 2H, 0H). 4.03(q, 8H, CH2). 7.34(m, 4H. Ar).
7.74(m, 4H, Ar), 10.28(s, 2H, meso).

cis isomer (23) 1H NMR (CDC13) 8-2.46(br s. 2H. NH). 1.78(t. 12H.

 

Me). 2.64(s, 12H, Me), 3.36(s, 2H, 0H), 4.o4(q. 8H, CH2), 7.34(m, 4H,
Ar), 7.73(m, 4H, Ar), 10.27(s, 2H, meso).

 

Trans-5,15-bi5(0-(pet-butylbenzoly)phenyl)-2,8,12,18-tetraethy1

 

-3,7,13,17-tetramethylporphyrin (23)

This compound was made in procedures analogous to those used in
generating the corresponding amidoporphyrin 2: 1H NMR (CDC13) 5’
-2.46(s, 2H, NH). 0.72(s, 9H, t-butyl), 1.75(t, 12H, Me), 2.64(s, 12H,
we), 4,01(q, 3H, 0H2). 6.45(d, 2H, Ar). 6.81(d, 2H, Ar). 7.64(m, 2H,
Ar), 7.87(m, 2H, Ar), 8.00(m, 4H, Ar), 10.17(s, 2H, meso).
Trans-5,15-bis(o-(m-(oC-N-imidazolyl)toluoyl)phenyl)-2,8,12,18-

 

 

tetraethyl-3,7,13,17-tetramethylporphyrin (46)

This compound was made from the trans diol porphyrin in procedures
analogous to those used in generating the corresponding amidoporphyrin
11. 1H NMR (coc13) 8-2.25(or s, 2H, NH), 1.69(t, 12H, Me). 2.24(s,

4". APCHZ), 2.60(s, 12H, Me), 3.96(m, 8H, CH2), 4.81(s, 2H, Im-H),
5.10(d, 2H, Ar). 5.96(d, 2H, Ar), 6.17(s, 2H, Im-H). 6.25(s, 2H,

73.

Im-H). 6.42(t, 2H, Ar), 7.00(d, 2H, Ar), 7.76(m, 2H, Ar), 7.91(m, 4H,
Ar), 8.23(d, 2H, Ar). 10.12(s, 2H, meso). '

74.

CHAPTER 2

THE SYNTHESIS AND CHARACTERIZATION

OF MULTINUCLEAR SYSTEMS DERIVED FROM

DIPHENYL PDRPHYRINS

or
C)”
in

be

0f

75.

Introduction

 

Many proteins contain more than one metal center. Often times
these metal centers act in concert to achieve the OVerall function of
the enzyme. Examples of metalloproteins containing more than one
metal center include: hemocyanin, copper oxidase, superoxide
dismutase, and cytochrome oxidase. The interaction of metal centers
can also produce interesting characteristics. In cytochrome oxidase,
the terminal component of the mitochondrial respiratory chain, studies
indicate that an iron and copper center are strongly magnetically
coupled. 32233

Simple porphyrins would serve as poor models for this and other
binuclear systems. .Aggregation is difficult to control and mixed
metal systems would be impossible to mimic. One method which we and
others have employed in the study of these multimetal proteins is
binuclear porphyrin systems.5'19'34”37 These systems incorporate
chelating ligands, which are covalently linked to the porphyrin ring.

The creation of one-to-one complexes of either fixed or variable
orientation can lead to interesting metal-to-metal interactions and
characteristics. Bridging ligands can also be incorporated to
investigate the potential of various groups to cause spin coupling
between metal centers.

This section describes the design, synthesis, and characterization

of several binuclear systems based on diphenyl porphyrins.

76.

211-22

The design and synthesis of cofacial diporphyrins has received
much attention over the past few years. 38-41 The fixed orientation
of the two porphyrin rings, over one another, provides an ideal
geometry for studying metal-metal interactions. These cofacial
porphyrins have found wide use as electrocatalysts for the cathodic
reduction of dioxygen to water, a process in principle similar to that
performed by cytochrome oxidase.

The general synthesis of previous cofacial diporphyrins has
involved the coupling of either two o-amino tetraphenyl porphyrins38.
or two 8-substituted porphyrins.39'41 The yields for the coupling of
meso phenyl substituted porphyrins are generally high but the distance
between the two rings is inherently large due to the nature of the
linkage. B-Substituted porphyrins allow the construction of dimers of
varing interplanar distances. The yields of these more versatile
systems are invariably lower due to the flopiness of the linkage side
chains and their tendency to polymerize. .

The smallest chain length for a symmetric dimer constructed from
ortho substituted tetraphenyl porphyrins was seven atoms in length38,
while Collman has prepared a B-substituted dimer with a three atom
linkage.41 The ideal system for oxygen reduction so far consists of a
four atom dimer (DP-4).

Our system involves a mixed porphyrin dimer, linking a
B-substituted diacetic acid porphyrin to the o-amino diphenyl

porphyrin system. The orientation of the amines in the cis compound

77.

is ideal for the formation of a dimeric species in high yield. The
use of the‘p-substituted porphyrin allows construction of a dimeric ,
species with an interplanar distance equal to the C5 dimers.' Although
this system is larger than the ideal C4 system, the increase in
rigidity obtained by incorporating the diphenyl ring system may lead
to a more favorable geometry.
Synthesis

The synthesis of the mixed cofacial porphyrin 29 involved the high
dilution coupling of the cis o-amino diphenyl porphyrin g’and the
p-substituted diacetyl chloride 42 in CH2c12 containing a small amount
of triethylamine, Scheme 4. The slow rate of reaction for the ortho
amino diphenyl porphyrin allowed the all-at-once addition of equamolar
quantities of both components followed by refluxing overnight. Hork
up of the reaction revealed large amounts of unreacted diamine,
indicating that much higher yields could be obtained under optimized
conditions. .

Metallation of the mixed cofacial diporphyrins proved difficult
due to the lower reactivity of the phenyl porphyrin inner protons.
The bis cobalt system was obtained by refluxing the free base in dry
THF with cobalt acetate. Similar treatment with copper acetate
produced only the monometallated adduct. The bis copper complex could
only be obtained if copper diamine porphyrins were used in the

coupling reaction.

78.

Scheme 4.

   

The difference in the acidities of the two porphyrins simplifies
the construction of mixed metal systems. The beta-substituted
porphyrin can be metallated with standard conditions, e.g., metal
acetate/Chzc12-methanol or acetic acid, without metallating the
diphenyl porphyrin.

Absorption Spectra

 

- The absorption spectra, Figure 14, proved valuable in correlating
observed results with previously observed trends for cofacial
diporphyrins.38'41 The diphenyl porphyrins exhibit a phyllo type
spectra, IV > 11> III) I, which is characteristic for mono or di-meso

substituted octaalkyl porphyrins. The beta-substituted derivatives

‘(IUO<
Ill

1H

79.

 

 

 

ABSORBANCE

 

 

 

300 400 500 600 700

Figure 1#. Electronic spectra of C dimethyl ester (42)
(....)3 (amino) DPE, cig (éfi (--—-); and mlxed
1n 2C

diporphyrin 29 E————). ' 12.

ii
fc
H

C0

of
‘(

res

80.

exhibit the typical etio type spectra, IV> III> 11> 1. Dimerization
was evidenced in the Soret band, representing the17-11*transition, by
1a blue shift of approximately 20 nm. This shift represents the
interaction of the two systems which are held in close proximity.
In the visible region the diporphyrin exhibited a slight red shift
with band broadening.

'1H NMR

 

As in our previous studies, 1H NMR has proven to be the most
powerful tool in verifying the structures of these complex systems.
The close proximity of the cofacial porphyrins to one another can
cause pronounced shifts in the resonances of nearby protons.

The free base spectrum of the mixed cofacial diporphyrin, Figure
15, indicates the formation of a highly symmetric species.

Diporphyrin formation was indicated by the shifts of the phenyl ring
protons, the unusual position of the resonances may be due to
constraint of the phenyl rings. The inability to form diastereomers
in this system was evidenced by the appearance of only three singlets
for the mesa hydrogens and only four ring methyl resonances. The
rigidity of the linkage was indicated by the AA' 88' system
corresponding to thecirprotons of the acetamide linkage.

The most pronounced feature of the spectrum was the up-field shift
of the inner pyrrolic hydrogens. The monomeric diphenyl porphyrin and
p-diacid porphyrin show single resonances at -2.5 and -4.0 ppm,
respectively, while the dimer exhibited a pair of singlets at -6.4 and

-7.7 ppm. the splitting reflected the dissimilarity between the two

81.

.maooo ea mm cfluseouoofio edema mo someeoom mzz :« ax: onm .mH magmas

ml #1 NI 0 N

o
PH’thlrb.P—>Lir>_D>>*r>»'_>>’r_‘PfibbbtrbfiLrLbbLfibb

 

 

 

 

.v

DPHHpPHFHh

 

 

 

>>>*

.w
.-..-.

LHFHr>>>P*>bfii—pb

 

82.

ring systems and the shift results from interaction of the neighboring
system. the size of the shift can be used in determining the
interplanar distance between the two rings4o, the closer the
proximity, the greater the interaction. The observed shifts indicated
an interplanar distance comparable to the 0P-4 diporphyrins, assuming
that the interaction of the diphenyl porphyrin was the same as for
simple 8-substituted porphyrins.

ESR, Metal-Metal Interactions

 

Electron spin resonance was used in the characterization of both
copper-c0pper and cobalt-cobalt complexes of the mixed cofacial
diporphyrin. The spectra, measured as toluene-CHZCI2 glasses at 77°K,
exhibited features indicative of interaction between the two metal
centers.

The spectrum for the bis copper mixed diporphyrin 20, Figure 16,
was very different from that of the well characterized monomeric
species, Figure 23A. The close proximity of the metal centers in
cofacial diporphyrins allows spin interactions to occur, producing for
the biscopper complexes a triplet spectrum.

Interactions between the two centers, indicates that the electron
exchange was faster than the resonance frequency (10105-1). Each
electron would then experience the total spin of the two metal
centers, 1 = 7 for Cu2+2. The seven hyperfine lines were weakly
discernable in the spectrum and were further split by zero field
splitting, (0), which arises mainly from electron-electron dipolar

interactions. Similar results have been observed by Chang40 and

83.

Sr .x mm pm ANHDN:0\oCm:HOp Rwy cofipsaom :muopm
Ca om cfiuhznuomflc cmxwm mo meQEoo AHHVSOIAHHVSO we Esmuoomm mmm .QH mpsmflm

 

 

ON

 

 

 

 

 

 

O..N o

 

 

84.

41, where D has been used to determine the internuclear

Collman
distance between the two metals. Recent results, however, indicate
that the metals tend to assume a slipped orientation in flexible
dimers.41
The biscobalt (111) complex of the mixed cofacial diporphyrin
exhibited no esr signal at 77'K. Reduction with dithionite followed
by addition of l-trityl imidazole produced a weak signal which was
enhanced by the addition of iodine, Figure 17. Analogous behavior has
been observed with other cobalt cofacial diporphyrins.40'41
The initial esr silent species represents the oxidized
Co(111)-Co(III) diporphyrin. In the presence of nitrogenous bases,
Equation 5, the reduced species binds oxygen to generate a tJ-peroxo
form which should also be esr silent but was inevitably contaminated
with small amounts of the lJ-superoxo complex, which can be
deliberately formed by oxidation with molecular iodine. The 15 line

isotropic spectrum reflects the coupling between the two 5 = 7/2

centers by the superoxo bridge.

(m )m
c)? 0'3.
_2_.1 (5)

 

85.

 

 

 

 

 

 

 

 

 

 

 

Figure 17. ESR spectrum of dioxygen adduct of the his

cobalt complex of diporphyrin 50 at room

temperature after addition ofa ~small amount
of I .
2

86.

Porphyrins with Metal-Chelating Appendages

A versatile model for cytochrome oxidase should incorporate
several features, most importantly; the ability to hold a copper and
an iron center in close proximity. In addition, the model should be
stable in the presence of oxygen or hydroxide, e.g., no Fe-O-Fe p-oxo
dimer formation, so that these ligands may serve as possible bridging.
In an effort to achieve such a system, several blocked and chelating
porphyrins were designed.

The effectiveness of the p-t-butyl phenyl group in preventing f;—

oxo dimer formation has been demonstrated. The p-keto amide linkage

shoulld also direct a chelating ligand over the porphyrin core in the
same fashion as the more “peptide-like“ blocking groups (malonyl
derivatives). Diphenyl porphyrin 21 was the initial target,
incorporating both chelating and blocking groups. The anionic nature

of the ligand was utilized to preclude the need of counter ions which

might interfere with metal interactions.

 

87.

 

Difficulties encountered in verifying the integrity of the p-keto
pyridyl porphyrin led to the development of alternate systems,
diphenyl porphyrin £3. The coordination sphere of this system was
very similar to EDTA. The butyl amide linkage would be less directed,
however, the increased flexibility would allow the two metal centers
to achieve an ideal geometry. Three porphyrins utilizing this amino
diacetic acid chelate were constructed. Initially a symmetric species
capable of coordinating three metals was constructed to develop the
synthetic pathway. The ligand was then attached to mono-blocked and
imidazole appended systems. The blocked system would prevent fI-oxo
dimer formation while the appended system would allow the study of the

influence of axial imidazole on promoting spin coupling.

Synthesis .
p-Keto Pyridine

The ligand 45 was constructed according to Scheme 5. The mono
methyl ester was easily generated from dipicolinic acid by the method
of Ooi and Magee.42 The crude acid chloride, resulting from.treatment
of the mono acid with thionyl chloride, was converted to the p-keto
acid by the method of Van Der Baan.43 Addition to a solution of
lithio bis-trimethylsilyl malonate at dry ice temperatures was
followed by careful hydrolysis with sulfuric acid. The mono
decarboxylated product was purified by washing with cold ether and

crystallization. The product was found to be unstable at room

temperature and slowly decomposed.

Scheme.5.

 

 

1) hello3
\
/ 2) Mel I
\ I ) > MeO / 01
3 5001 u N
11020 N 00211 2 o
1) 1.1c1((cozsui¢13)2 ' \ _
p. /

89.

‘All attempts to generate the acid chloride of the unstable B-keto
acid failed, generally resulting in black solutions which probably
resulted from rapid ketene formation.

Eventually two routine peptide forming reagents proved successful
in coupling the o-amino phenyl porphyrins with the p-keto acid.
Dicyclohexylcarbodiimide (DCC) and bis imidazole carbonyl (1m2co) were
both effective in amide formation, but at different rates. A CH2c12
solution containing equimolar quantities of DCC, 8-keto acid, and
porphyrin resulted in quantitative yields after 1h at room
temperature. Similar results with Imzco would only be obtained if the

reaction were allowed to proceed for several days. The effectiveness

of DCC was surprising, since others have reported the failure of this
reagent in reacting with other o-amino phenyl porphyrins due to steric
congestions?4 He, as well, have not found widespread application of
this coupling.reagent in diphenyl porphyrins.

The formation of one species by both reagents was indicated by tlc
of the free base and zinc complex in a variety of solvents and solid
phases. Initial 1H NMR data showed the presence of a mixture of
compounds, which could not be separated. Extensive 1H NMR studies
eventually proved the integrity and the singular nature of the
reaction product from both coupling reactions.

The pyridine ester was easily hydrolysized with methanolic sodium

hydroxide.

90.

'* Amino Diacetic Acid .

The amino diacetic acid ligand was constructed onto the porphyrin
in a stepwise fashion, Scheme 6. Efforts to construct the ligand
prior to coupling with the porphyrin failed due to the instability of
the tertiary amine. The protected amino butyric acid was linked to
the o-amino phenyl porphyrins by a mixed anhydride process using ethyl
chloroformate and triethylamine in toluene. The yields of the
coupling reaction were routinely low, ca. 35%, however, the only other
porphyrin recovered was the starting material.

Initially the carbobenzyloxy (C82) protected butyroamino acids
were used. Their resistance to acid hydrolysis and inconsistent
results with catalytic hydrogenation in deprotection led to the use of
t-butyloxy carbamide (t80c) systems.

Purification of reaction mixtures by extraction with 80%
phosphoric acid led to premature hydrolysis of the t80c group.
Purification of the very polar free amine was avoided by initial
purification of the reaction mixtures on protonated silica columns.
Hydrolysis of the purified protected amine proceeds quantitatively in
CHI/acetic acid.

The free amines react readily with ethyl bromoacetate in refluxing
acetonitrile-CHZCI2 containing a small amount of triethylamine. Short
reaction times or lack of base led to isolation of monoesters.
Hydrolysis to the diacid was easily achieved with methanolic sodium

hydroxide.

91.

 

 

on: .m: a

.885 .xuogoizaox/

 

 

.o mamnom

92.

This Sequence of reactions led to the formation of the symmetrical
tetraacid, 23,which was water soluble, as well as the mono t-butyl
benzamide blocking and chelating systems. The trans
appended-imidazole was carried out to the free amine stage, however,
lack of sufficient material after hydrogenation of the 082 protecting
group precluded completion of the synthesis.

Metallation of the systems prior to hydrolysis of the esters
produced only the metallo-porphyrin species, as evidenced by epr.
Following hydrolysis, the ligands were metallated with copper acetate,
which is epr silent due to dimerization.

1H NMR

1H NMR of the free base porphyrins were routinely used to verify
the integrity of products and precursors in the reactions leading to
protected-chelating porphyrins.

The 1H NMR of the free pyridyl 8-keto acid, §§, reveals the
presence of enolization by the appearance of vinyl hydrogens, 86.4
ppm, and the reduced intensity of the cirmethylene signal, integration
of 1.2 vs. 3 for the methoxy protons. The pyridyl hydrogens appear as
a multiplet centered at 58.0 ppm.

The spectrum of the coupled product in CDCl3 at room temperature
showed two species, Figure 188, a symmetric and an unsymmetric in a
ratio of 1:4, respectively. The mixture was indicated by the doubling
of all signals, except the ring methyls which point toward the

symmetry of the species.

93.

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94.

p b b * H _ ’ ’ ’ ’ 1—7 H ? P p F H ’ R r —i L 7 H ’ P ’ 7 D D P 7 L H H P 7 b F T I 2 F L h L F H )h’ b } 7 ‘ h L }

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2.53. i a

 

95.

AAfter chromatography failed to separate or vary the composition of
' the mixture, several perturbations were made on the system and the
responses were followed by 1H NMR. The following experiments failed
to alter the ratios consistently:

1. Temperature variations, -50 - +50°C.

2. Dilution studies, 20 fold changes.

3. Addition of methanol - d4,

4. Metallation, Zn, followed by addition of excess imidazole.

5. Protonation, TEA/020.

Eventually the use Of toluene-d8 produced a spectrum reflecting
one species, Figure 180. The AA'BB' quartet observed for the phenyl
blocking group was indicative of hindered rotation due to aggregation,
as observed previously for the cis bis p-t-butyl benzamide system.
Having shown that one species was formed, re-examination of the 00013
spectrum revealed identity of the complex. The methyl ester, oc-

methylene, and enol hydrogens observed in the free ligand were all
evident in the coupled complex although at slightly shifted positions.
The pyridyl hydrogens are shifted far upfield due to the interaction
with the porphyrin ring current. The triplet and doublet of the
pyridyl ring, 83.4 and 3.6 ppm, respectively, shift back downfield to
straddle CDc13 when TFA/DZO was added to the system, Figure 18A. The
changes reflect the disruption of the interaction when both aromatic
ring systems become protonated.

The nature of the components of the mixture in CDCI3 are unknown,

however, it can be speculated that the highly symmetric species

96.

represents some type of dimeric form. It would be otherwise
impossible to explain the high symmetry observed for an unsymmetrical
molecule when the ring methyls have always served as extremely
sensitive probes.

Amino Diacetic Acid

 

The high symmetry of the trans tetraacetic acid porphyrin and its
precursors simplified assignment of resonances and identification of
reaction products, Figure 19. The coupling of the CBz-protected
butyroamino acid to trans bis o-amino DPE was indicated by the usual
downfield shift of the phenyl protons and the appearance of side chain
resonances.

Deprotection of the amine produced large upfield shifts in the
side chain resonances. This displacement was due to the coordination
of the free amine to the amide NH, exposing the 8 and oL-methylenes to
the porphyrin ring current. Evidence for this coordination was also
indicated by the corresponding shift of the amide proton during the.
reaction sequence.

Similar trends were observed in the synthesis of the blocked and
imidazole tethered derivatives, Figures 20 and 21. The lack of
symmetry in these systems caused splitting of the ring methyls and
produced complex patterns in the aromatic region.

The 1H NMR of paramagnetic metallated species, e.g., Cu and Fe,
are inherently broadened and offer little structural data. The
sensitivity of the isotropic shifts to the spin density of the metal

would make the method ideal for probing the interaction between two

97.

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101.

'metalcenters.45 Unfortunately, few studies have been performed on
mixed metal systems to enable correlation of potential results.
Electronic Spectra, Binuclear Chelating Hemes

The electronic speCtra of the chelating systems were
dominated by the porphyrin rings. The chelating appendages have
little effects on the visible or Soret region of the free base or
metallated species, except to provide potential ligands.

Gunter and Mander6

have used changes in the electronic spectra as
evidence for the incorporation of metals into their binuclear diphenyl
heme hydroxides. Similar changes were observed for the

blocked-chelating ferric hydroxides upon the addition of copper salts,

Figure 22. However; similar treatment of non-chelating hemes, e.g.,
trans bis(p-t-butyl benzamide) DPE ferric hydroxide, produced
identical spectral changes. The deviations in the spectra merely
reflect the metal catalyzed ligand exchange in hemes and cannot be

used to verify metal chelation at the appendages.

 

ESR - Binuclear Systems

Electron paramagnetic resonance was used to probe the ability of
the chelating ligands to bind Cu(II) and investigate possible spin
interactions between the two metal centers.

The esr spectra of the bis copper adducts of the p-keto pyridyl
and amino diacetic acid protected porphyrins, Figure 23, showed no
coupling between the .wo metal centers. The upper trace represents
the spectra of the monomeric copper porphyrin, 43, and the lower trace

the effect of adding copper acetate and washing with water. Although

102.

2000‘

l
(
I
I
l
l5.0-' l :
l
l
I
l
l

5.0‘

 

 

 

300 400 500 600 700

Figure 22. Electronic spectra of the Fe(III)PCl complex
of diphenyl porphyrin 53 ( )1 and the
effect of adding Cu(II7”acetate to the sample

 

103.

no coupling was observed, the intensity changes indicated that
metallation of the amino-diacetic acid ligand did occur. Similar
experiments on the B-keto system produced the same-results. The lack
of coupling in these blocked systems may reflect the random geometry
of the metal centers. '

The nature of the chelating ligands were more easily determined
using a diamagnetic porphyrin, e.g., zinc or nickel systems. Efforts
to use zinc porphyrins in c0pper chelating reactions resulted in trans
metallation, as evidenced by the resulting characteristic Cu(11)
porphyrin spectrum. The use of the less labile nickel porphyrins

produced the desired results, Figure 24. The uppper trace represents

the Ni(II) porphyrid and unmetallated B-keto pyridyl system, i}, the
weak signal was probably due to small impurities. Treatment with
copper acetate produced the lower trace which shows a typical axial
copper spectrum.

The mixed heme-copper complexes were constructed to investigate
possible interactions. Treatment of the ferric hydroxide of the
protected amino diacetic acid system, §3, with copper acetate produced
the binuclear system, Figure 25.

The overlapping Cu signal, 9 = 2, failed to disappear after
numerous washings with water.

Conclusions and Further Hork

 

The utility of the diphenyl porphyrin system in its ability to

construct binuclear systems has been demonstrated. Mixed cofacial

Figure 23.

104.

 

 

ESR spectra of blocked and chelating diphenyl
porphyrin 3, (A) Cu(II) porphyrin- diacid;.

(B) Cu(II)- u(II) complex. Spectra measuredo
in frozen solution (5% toluene/CH2C12) at 77 OK.

Figure 24.

 

105.

 

ESR spectra of blocked and chelating diphen l
porph rin 51. (A) Ni(II) porphyrin-acid; (B
Ni(II porphyrin Cu(II) complex. Spectra

measu ed in frozen solution (5% toluene/CH Cl )
at 77 K., 2 2

106.

 

 

 

 

 

 

 

 

 

 

 

Figure 25. ESR spectra of blocked and chelating di henyl
porphyrin 3. (A) Fe(III)PCl-diacid; (B
Fe(III)PCl- u(II) complex. Spectra measured

in frozen solution (5% toluene/CHZClz) at
77°K.

107.

diporphyrins have been constructed-in high yield and the bis cobalt
complexes of these systems may act as electro catalysts for the
cathodic reduction of oxygen to water. This highly rigid system can
be exploited further in creating unique inorganic complexes or
bio-inorganic models. I

The ability to construct non-porphyrin chelating ligands onto
these diphenyl porphyrins has also been shown. The exact structure of
these systems awaits further characterization. Although no spin
coupling was observed in bis copper and iron-copper complexes, the
addition of bridging ligands may promote such interaction. The

bridging ligands may be added as extraneous species in solution or

covalently attached'to the porphyrin at the expense of the blocking
group. In general, the characterization and exploitation of these
multinuclear systems has only just begun.

Experimental (Binuclear Systems)

 

Mixed Dimer (£9)

The C8 Dimethyl ester (500 mg) was dissolved in formic acid (40
ml) containing hydrochloric acid (3 ml). The solution was refluxed
for 2 h before being poured into ice. Extraction with methylene
chloride was followed by neutralization. Evaporation gave the crude
diacid.

The crude diacid (100 mg) was dissolved in methylene chloride (100
ml) and deareated with nitrogen. Excess oxalyl chloride was added and
the mixture was refluxed for 1 h or until tlc after quenching with

methanol revealed no acid.

108.

The crude acid chloride, (100 mg of acid) and cis amino diphenyl
porphyrinlg’(923mg) were combined in 2 e of dry methylene chloride
containing 2 ml Et3N. The mixture was refluxed overnight, then
quenched with water. After separation, the organic layer was reduced
to 100 ml and washed to remove the Et3N. The solution was then dried
over sodium sulfate and eluted through a short silica gel pad with 22
MeOH/CHZCIZ- Separation on thick layer silica gel plates resulted in
80 mg dimer and 40 mg recovered diamino porphyrin. The nonpolar dimer
which does not fluoresce was recrystallized from CH2012/Me0H. 1" NMR
(c0013) 5-7.71(s. 2H, NH), 1.0-2.2(m, 42H, CH2, Me), 2.38(s, 6H, Me),
2.40(s, 6H, Me), 3.36(s, 6H, Me), 3.6-4.4(m, 12H, CH2). 4.61(d, 2H,
-CH2), 5.06(d, 2H, 0H2). 6.33(d, 2H, Ar), 7.06(t, 2H, Ar). 7.77(t, 2H,
Ar). 8.60(s, 2H, NH), 8.89(s, 2H, meso). 9.06(s, 2H, meso).9.22(d, 2H,
Ar). 9.35(s, 2H, meso).

Trans-5, 15-bi s(o-(N-CBZ- y-aminobutyramidomhenyl)
-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (59)

A mixture of CBz-diaminobutyric acid (182 mg, 0.76 mmol) and
triethyl amine (78 mg, 0.77 mmol) in dry tolulene (15 ml) was cooled
to 0°C under nitrogen. A solution of chloro ethyl formate (82 mg, 76
mmol) in toluene (10 ml) was added dropwise to the cold solution
during ca.0.5h; afterward, the mixture was allowed to warm to room
temperature for ca. 1h.

Trans-o-diamino porphyrin l (74 mg, 0.114 mmol) in dry THF (20 ml)
was added dropwise at room temperature. After completing the

addition, the mixture was refluxed for 3 h. The solvent was removed

109.

in vacuo and the residue redissolved in CH2012 and washed successively
With 103'HC1, H20, NaHC03 (sat. aqueous). After evaporation the
residue was purified onthick layer silica gel plates eluted with 52
MGOH/CHZCIZ. The least polar band corresponds to the Cszrotected
amine. 1H NMR (c0c13) 8-2.33(or s, 2H, NH). 1.‘05(q, 4H, CH2).1-40(t.
4H. CH2), 1.78(t, 12H, Me). 2.35(m, 4H, CH2), 2.52(s, 12H, Me),
3.67(t, 2H, NH). 3.80(S, 4H, ArCHz). 4.02(q. 8H, CH2). 6.44(d, 4H.
Ar). 6.97(t, 4H, Ar), 7.03(m, 2H, Ar), 7.18(S, 2H, NH), 7.50(t, 2H,
Ar), 7.82(m, 4H, Ar). 8.71(d, 2H, Ar), 10.26(S, 2H, mESO).

Trans 5, 15 bis(o-( fl-aminobutgyramidomhenyl )-2 ,8 , 12, 18-

 

tetraethyl-3,7,13,17-tetramethylporphyrin (52)

 

The diCBz porphyrin 56 (20 mg) dissolved in formic acid (15 ml)
was hydrogenated at 1 atm using Pd/charcoal (5 mg) for 3-5 h. The
mixture was diluted with water, neutralized with 10% NaOH and
extracted With CH2C12° The crude product was purified on thick layer
silica gel plates with 5: MeOH/CHZCIZ. 1H NMR (CDC13)«S-2.5(br s, 2H.
pyrrole NH). -0.05(br, 2H, NHZ), 0.80(m. 4H, CH2), 1.35(t, 4H, CH2).
1.52(t. 4H, CH2). 1.78(t, 12H, ME). 2.54(S, 12H, Me). 4.03(q, 8H,
CH2), 7.49(t, 2H, Ar), 7.82(m, 4H, Ar), 8.15(s, 2H, NH). 8.72(d, 2H,
Ar), 10.06(s, 2H, meso).

Trans 5,15 bis(o-(n,N-bis)ethyl acetate)-X-aminobutyramido)-

 

2,8,12,18-tetraethyl-3,7,13,l7-tetramethylporphyrin (53)

 

A mixture of the diamine 51 (10 mg, 0.022 mmol) and an excess of
ethyl bromoacetate in methylene chloride (10 ml) and acetonitrile (10

ml) containing Et3N (1 ml) was refluxed for 1.5h. Evaporation to

110.

“dryness and purification on thick layer plates produced the
tetraacetate in’_9oz yield. 1H NMR (coc13)8-2.4(or s, 2H, NH),
0.63(t, 12H, OEt). 1.29(m, 4H, CH2), 1.52(t, 4H, CH2). 1.80(t, 12H.
Me). 2.02(t. 4H. CH2), 2.57(s, 12H, Me). 2.70(s, 8H, CH2), 3.22(q, 9H,
OEt), 4.03(m, 8H, CH2), 7.09(s, 2H, NH). 7.70(t, 2H, Ar), 7.76(d, 2H,
Ar), 7.83(t, 2H, Ar). 8.79(d, 2H, Ar). 10.28(s, 2H, meso).

Trans 5-(o-( oL-N-imidazolyl)toluamido)phenyl)-15-(o-(N-CBz-‘8—

 

aminobutyramido)pheny)'2,8,12,18-tetraethyl-3,7,13,17-tetramethylporp

 

12:11 (9,0,)

This porphyrin was made in the same fashion as the trans bis C82
56. 1H NMR (00013)8-2.34(or s, 2H, NH), 1.08(m, 2H, CH2). 1.42(m.
2H. CH2), 1.73(m, 12H, Me), 2.38(m, 2H, CH2). 2.52(s, 6H, Me), 2.58(s,
6H, Me). 3.23(s, 2H, ArCHz). 3.72(s, 2H, ArCHz). 4.00(m, 8H, CH2).
5.09(s, 1H, Im-H), S.72(s, 1H, Im-H), 6.2-6.6(m, 5H, Ar, Im-H, NH).
7.5-8.0(m, 7H, Ar, NH), 8.71(d, 1H, Ar). 8.95(d, 1H, Ar). 10.27(s, 2H,
meso)..

Trans 5-(0-(ot-N-imidazolyl)toluamido)phenyl)-15-(o-(‘23

 

aminobutyramido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-

 

tetramethylporphyrin (4})

 

The mono CBzcx-Im 99 was deprotected according to the previous
method to give a trace of this free amine. 1H NMR (CDC13)5-2.4(br 5.
2H, NH), 1.0-1.6(m, 6H, CH2), 1.75(m 12H, Me), 2.53(s, 6H, Me).
2.61(s, 6H, Me). 3.32(s, 2H, ArCHZ), 4.0(m, 8H, CH2). 5.16(br s, 2H.
NH). 5.77(s, 1H, Im-H), 6.20(s, 1H, Im-H). 6.32(d, 1H, Ar), 6.40(t,
1H, Ar), 6.50(d, 1H, Ar), 6.60(s, 1H, NH), 7.4-8.0(m, 7H, Ar), 8.69(d,

1H, Ar). 8.98(d, 1H, Ar), 10.28(s, 2H, meso).

_ 111.

Trans 5-(o-( ot-N-imidazolyl )toluamido)ph’enyl )-15-(o—(N-t80c-3’_- _
a~aminobutyramido)phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporp
£1513 (58)

The mixed anhydride coupling was used involving 155 mg t80c, 100
mg Et3N, and 100 mg t-butyl porphyrin 5; Purification was performed
on protonated silica columns using 102 acetic acid/CH2c12 to elute
unreacted amino acid. The porphyrins were eluted with 102
methanol/CH2c12. After washing with 5% NaOH, then purified on thick
layer plates to yield: 1H NMR (c0013) S-z.35(br s, 2H, NH). 0.74(s.
12H, tBu), 0.96(s, 12H, t80c), 1.10(m, 2H, CH2), 1.38(t, 2H, CH2),
1.76(m, 12H, Me). 2.44(m, 2H CH2). 2.55(s, 6H, Me), 2.59(s, 6H, Me).
4.04(m. 8". CH2). 6348(s. 4H, Ar). 6.97(s, 1H, NH). 7.54(t, 2H, Ar).
7.7-7.9(m, 3H, Ar), 8.0(s, 1H, NH). 8.73(d, 1H, Ar). 9.09(d, 1H, Ar),
10.30(s, 2H, meso).

Trans 5-(0-(p-t-butylbenzamido)phenyl)-1S-(o-(8’-aminobutyramido)
phenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (88)

The purified t80c protected porphyrin 88 was dissolved in acetic
acid (20 ml) containing HCl (2 ml) and stirred at room temperature for
10 min. Diluted with water, neutralized, and extracted with methylene
chloride to give quantitatively 88. 1H NMR 8-2.35(br s, 2H, NH),
0.74(s. 12H, tBu). 1.24(m, 2H, CH2). 1.53(t, 2H, CH2),1.76(m, 12H.
M8). 2.31(t, 2H, CH2), 2.56(s, 6H, Me), 2.59(s, 6H, Me), 4.02(s, 1H,
NH), 4.20(m, 8H, CH2), 6.47(s, 4H, Ar). 7.54(m, 2H, Ar), 7.8-7.9(m,
4H, Ar), 8.00(5, 1H, NH), 8.79(d, 1H, Ar), 9.09(d, 1H, Ar), 10.28(s,

2H, meso).

112.

Trans-S-(o-(p-t-butylbenzamido)phenyl)-15-(o-(N,N‘bisethylacetate)-ZL'

 

aminobutyramido)phenyl)-2,8,12,18-

 

tetraethyl-3,7,13,17-tetramethylporphyrin (£8)

The free amine protected porphyrin was treated in the same fashion
as the trans diamine §Z° 1H NMR (00013) 8-2.37(nr s, 2H, NH), o,53(t,'
6H, 0Et), 0.74(5, 12H, tBu). 1.27(m, 2H, CH2), 1.52(t, 2H, CH2).
1.76(m, 12H, Me), 2.03(t, 2H, CH2). 2.57(s, 6H, Me), 2.59(s, 6H, Me),
2.71(s, 4H, CH2). 3.21(Q. 4H, 0Et), 4.03(m, 8H, CH2). 6.47(s, 4H, Ar),
7.26(s, 1H, NH), 7.48(m, 2H, Ar). 7.5-7.9(m, 4H, Ar). 8.0(5, 1H, NH).
8.77(d, 1H, Ar), 9.09(d, 1H, Ar). 10.28(s, 2H, meso).

Methyl 2-( B-carboxyl)acetyl-6-carboxylatepyridine (55)

Methyl 2-carboxypyridine-6-carboxylate (Z-methyl dipicolinate) was
prepared from dipicolinic acid via the silver salt according to Ooi
and Magee.42 The monacid monomethyl ester (3 mg) was suspended in
benzene and treated with an excess of thionyl chloride (10 ml). The
mixture was stirred at 50°C for 8 h. By the end of this period, all
the solids had dissolved. The solution was evaporated to dryness and
the resultant acid chloride, m/e 200, was used without further
purification.

Methyllithium (28.5 mL, 1.4 M) was added dropwise to a solution of
bis(trimethylsilyl)malonate (9.64 gm, 38.9 mmol) in ether (77 ml)
under argon at -78°. Following the addition, the solution was allowed
to warm to 0', and the above acid chloride (3.8 gm, 19 mmol) dissolved
in THF (40 ml) was added. The solution was stirred for 10 min and a

cold solution of aqueous sodium bicarbonate (5%, 20 ml) was added.

113.

The mixture was thoroughly shaken before the aqueous layer separated.
It was acidified carefully to pH 2 with cold 4N H2504, then extracted
repeatedly with ether (3 x-100 ml). The organic phase was separated,
dried, and evaporated to give the crude keto acid. Decarboxylated
impurities (mostly 2+acetylpicolinate) were removed by washing with

cold ether. The keto acid was recrystallized from CH2c12 to give

white needles. m.p. 120-121’; 1

H NMR (CDC13-acetone d6) 63.96(s, 3H.
0CH3). 4.20(s, 2H, CH2). 8.20(m, 4H, pyr.); mass spectrum (70eV) M/e
179(M+-C02). calcd 223.
Trans-S-(o-(p-t-butylbenzamido)phenyl)-15-(o-(methy1
2-8-carboxyl)acetyl-6-carboxylamido)pyridine)phenyl)-2,8,12,18-

tetraethyl-3,7,13,17-tetramethylporphyrin (58)

 

To a solution of porphyrin s (20 ml, 0.025 mmol) in 0Hzc12 (50 ml)
was added an excess of the B-keto acid (22.3 mg, 0.1 mmol) and DCC
(20.6 mg, 0.1 mmol). The solution was allowed to stir at room
temperature for 3 h or until completion of the reaction as indicated
by TLC. Hater was added and the organic layer separated, washed
successively with 10% HCI, water, 52 NaOH, and dried. After
evaporation, the crude solid was recrystallized from CH2012'hexane to
afford a red powder, yield 23 mg, 94%. m.p. 250°C. 1H NMR (toluene
d8)¢S-3.1(br s, 1H, NH), -2.1(br s, 1H, NH). 0.28(s. 9H, t-Bu).
1.70(t, 6H, Me), 2.54(s, 6H, Me), 2.77(s, 6H, Me), 3.00(s, 3H, DMe).
3.08(t, 1H py). 3.50(s, 2H, CH2), 3.58(d 1H, pyl), 3.80(m, 8H, CH2).
5.21(d, 1H. py). 5.87(d, 2H, Ar), 6.46(d, 2H, Ar), 7.23(t, 1H, Ar),
7.35(t, 1H, Ar), 7.48((d, 1H, Ar), 7.60(t, 1H, Ar). 7.74(t, 1H, Ar).

114.

7.82(d, 1H, Ar), 8.12(s, 1H, NH), 8.68(d, 1H, Ar), 8.72(s, 1H, NH),

9.57(d, 1H, Ar), 10.29(s, 2H, meso). Anal. Calcd. for c68"80"8°6c' H

6.58, N 9.55; found C 76.11, H 6.38, N 9.32

115.

CHAPTER 3

THE SYNTHESIS AND CHARACTERIZATION

OF SIMPLE AND DERIVATIZED GEMINAL
ALKYLATED HYDROPORPHYRINS

116.

Introduction

Hydroporphyrins, porphyrins which are partially reduced, occur in
a wide variety of proteins and enzymes. Chlorins (48). (dihydro-
porphyrins) and bacteriochlorihs (48),(tetrahydroporphyrins) have been
studied extensively due to the presence of their magnesium complexes
as the essential chromophoric units in the photosynthesis of algae,

45

plants, and bacteria. Isobacteriochlorins (64), compounds with

adjacent rings reduced, have only recently been found in nature 46 and
hence have been studied less extensively. The iron complex, siroheme
(88), has been found to be the binding and active site of several
assimilatory and dissimilatory sulfite and nitrite reductases.46’47
The demetallated form, sirohydrochlorin, has also been identified as a

48-50, a corrin.

key intermediate in the biosynthesis of Vitamin 812
The scarcity of naturally occurring material promotes the use of
model systems of comparable oxidation state in determining why nature

has utilized these reduced systems. Hydroporphyrins, as the name

Rt

 

117.

implies, result from hydrogenation of the porphyrin macrocycle. The
di and tetrahydro derivatives can be generated by a variety of

reductive techniques51

on porphyrins and metalloporphyrins, including:
catalytic hydrogenation, diimide, and dissolving metal. These hydro-
derivatives undergo facile dehydrogenation to the more unsaturated
chlorins and porphyrins.52 This instability to mild oxidizing agents
is characteristic of most naturally occurring chlorins and
bacteriochlorins. However, several chlorins and siroheme are

stabilized by alkylation.

He have devised a method for constructing gem-di-alkylated hydro-
porphyrins such as siroheme and the chlorin, heme d53'57. thCh are
resistant to mild oxidation. This route has led to the synthesis of
both simple and more complex models of the hydroporphyrin family. The
characterization of these systems will hopefully help in understanding
what special competence these reduced systems have which is required
to perform their unique function in nature.

Oxidation-Reduction.

Inhoffen and coworkers58 initially synthesized oxo-analogues of
hydroporphyrins by the oxidation of octaethylporphyrin (OEP). The
geminal ketones produced were isolated and fully characterized by
visible and 1H NMR. He have modified their procedures to maximize the
formation of these key intermediates by a similar reaction sequence.59
The reaction involved oxidation of the peripheral double bonds to form
vicinal diols which rearrange in the presence of acid to form geminal
alkylated ketones of varying substitution patterns. A fully symmetri-

cal species, such as OEP, will produce one monoketone, Six diketones,

118.

and four triketones, Scheme 7; An isophlorin, 13: resulting from the
oxidation of trans methine positions, was also isolated. The yield of
each component reflects the degree of steric congestion generated by
geminal alkylation.

Isolation of the ketones from the complex mixtures involved
separation on numerous silica and alumina plates and columns. The
crude mixture was initially separated into two fractions using a
silica column. The first fraction was eluted with 252 CHZCIZIhexane
until the eluent became green, signaling the second fraction. Each
fraction was further separated on plates or columns until components
were pure by visible spectroscopy. Almost all ketones can be purified
to the point of producing crystals from CH30H/CH2c12, The 2, 3
diketone (48). however, was always contaminated by triketones and
purification could only be achieved by decomposition of the impuri-
ties. The triketone was found to react more rapidly with alkyl
lithiums, resulting in isolation of pure diketone after chromato-
graphy.

The ketones serve as poor models to naturally occurring
hydroporphyrins, due to the dominance of the carbonyls which are in
conjugation with the aromatic ring system, but are versatile
intermediates in the construction of model systems. Simple systems
can be constructed by the reduction of the carbonyls to alkyls or
hydrogens.

Our initial studies on these reduce systems involved alkylation of’
the ketones with alkyl lithiums and reduction of the resulting

benzylic type alcohols. These sterically hindered alcohols were

resistant to reduction and readily eliminated to the exo-methylene

119.

Scheme 7.

 

 

120.

compounds which extend the conjugated system. The reduction of the
methylene can be achieved in low yields with catalytic hydrogenation.
Alternatively, the alkene or alcohol can be reduced in good yields by
a modification of the reductive alkylation procedure developed by

MacDonald50 for alkylating pyrroles.
The reagent, which should be freshly prepared, is composed of a

mixture of hydriodic acid, acetic acid, and hypophosphorous acid in a
10:10:1 ratio, respectively. This mixture was added to an acetic acid
solution of the alcohol containing a small amount of ascorbic acid.
The reaction was warmed to 60‘ for a few minutes, and then was
quenched by diluting with water. This method has found general
success in the reduction of chlorin and isobacteriochlorin benzylic-
type alcohols, Equations 6, 7, however, failed to reduce the corres-

ponding bacteriochlorins.

 

(6)

 

(7)

 

Z?
The bacteriochlorins represent that least acidic and stable of the
reduced porphyrin series. Treatment of their benzylic-type alcohols

with the hydriodic acid reagent produced the corresponding alkenes

121.

initially, which decomposed after longer reaction times. Catalytic
hydrogenation of the alkenes produced small amounts of the reduced
species, as evidenced by visible spectroscopy, however isolation of
small quantities of the unstable material proved difficult.

The only method found to be effective in the formation of the
reduced species was diimide reduction of the alkene, Equation 8. This
reduction, which was also employed by Hhitlock and 0ester61 to produce
hydroporphyrins from tetraphenyl porphyrins, involves the gradual
generation of diimide. Tosyl hydrazide was added portion wise to a
pyridine solution of the porphyrin containing potassium carbonate.

The competing disporportionation was impeded by maintaining a low

concentration of diimide. Progress of the reaction was easily
monitored by visible Spectra of the reaction mixture. Purification of

the light sensitive reduced species was carried out in the dark on an

alumina column to yield the reduced species in good yield.

(8)

 

 

wand Appended Systems
In an effort to study the binding properties of hydroporphyrin—-
type heme systems, several derivatized hydroporphyrins were designed
and constructed. The use of covalently linked imidazoles allows the
kinetic study of 02 and CD binding to reduced hemes. The high local

concentration of ligahd also allows the Study of mixed ligand systems

122.

not possible with unappended porphyrins.

Attempts to utilize the benzylic-type alcohols, 11, in ester
couplings failed due to facile elimination, again, owing to thesteric
congestion. The alcohol 88, resulting from lithium aluminum hydride

reduction of the ketone, cannot eliminate exo to the porphyrin ring,

however, coupling reactions only resulted in complex mixtures which
62

may be due to initial isochlorin formation.

  

L9

 

Our initial route to chlorins with appended imidazoles involved
the treatment of the ketone with the lithium enolate of ethyl acetate
to produce the chlorin hydroxy ester, 83, which was easily reduced
with the hydriodic acid reagent. Hydrolysis to the acid, 88, was

The low yields associated with hydrolysis and acid chloride
formation led to the study of alternate techniques in attachment of

the side chain. Utilization of the lithium dianion of the acetyl
derivative of 4(N-imidazolyllbutyl amine produced low yields, as did
the use of the lithium enolate of the N(isopropyl), N(acetyl)
derivative. Hittig reactions involving the generation of the unstable
yield of ethyl-p-triphenyl phosphonium proprionate in the presence of

the zinc mono ketone also proved unsuccessful.

Eventually the step-wise synthesis was modified to eliminate the

123.

rigorous treatment of the chlorin nucleus, Scheme 8. The ester
chlorin was readily reduced with lithium aluminum hydride to produce
the corresponding alcohol, 23, in quantitative yield. The alcohol was
easily coupled with a variety of imidazolyl acid chlorides to create

imidazole appended chlorins, 28-28, of varying chain length.

 

Scheme 8.
OE!
l) L'°"z°°z" _ LIAUH‘
2)HOAc. H3P02.Hl THF
° "(0" ) lml
ln(CHanOCI z "
n- “243

 

Derivatized isobacteriochlorins have also been synthesized by a
similar route, Scheme 9. Monoalkylation of the 2, 3 diketone (48) was
achieved by the dropwise addition of methyllithium to an ethereal
solution of the ketone at room temperature. Usually an excess of
methyllithium was required to initially destroy the triketone
impurities which seem to react faster than the corresponding diketone.
Careful monitoring by TLC results in a statistical mixture of mono-,

di-, and unalkylated diketone.

124.

 

 

 

 

 

SCheme 9. o E I) "3. "3’0! 0
ll 1.. not: ' won.
a) LIGchottT a) LOMH‘ v
o
68
~
w
on
clcoccwl )1).
w
100 101
~ ~

Separation of the mono alkylated species, 28, followed by
treatment with excess ethleTithio acetate produced the dissimilarly
substituted diol, 28. The diol was unstable to light and air and
should be reduced soon after formation, alternatively, the sterically
congested intermediate can be Stabilized by treatment with mesyl

chloride to yield the eliminated species, 21. The diol or alkene was

reduced with the hydriodic acid reagent to produce either the mono- or
di-reduced species. Analysis of the mono reduction products, 22!
indicate that the methyl substituted benzylic-type alcohol was reduced
initially, followed sluggishly by the ester alcohol. The strongly
hydrogen bonded beta hydroxy ester system was evident in the IR and 1H
NMR spectra. The coordinated carbonyl appears at 1700 cm"1 and the
hydroxyl at 3480 cm.1 in the mono reduced species, while the doubly

1 and no hydroxyl

reduced system shows the free carbonyl at 1760 cm’
absorption. In the 1H NMR the methylene of the rigid p-hydroxy ethyl
acetate, Figure 26, appears as an aa'bb' system and as a simple

quartet in the fully reduced system.

 

Figure 26. Hydrogen bonding in chlorin and isobacteriochlorin ethyl
acetate-alcohols.

The fully reduced system was then treated with lithium aluminum
hydride to yield the primary alcohol. 499, which readily coupled with
acid chloride imidazoles.

Absorption Spectra

The visible spectra of reduced porphyrins have been well
characterized and were routinely used in the identification of ring
systems. In general, chlorins have a narrow red band around 650 nm
and a Soret three times as intense. Bacteriochlorins have an intense
signal around 700 nm and a split Soret. Isobacteriochlorins are
characterized by multiple bands in the Soret region and a series of
four bands on increasing intensity followed by a weak band around 640
nm. Table 8 lists the visible spectra of some of the model

hydroporphyrin systems which were constructed.

The dominance of the carbonyls in conjugation with the system
for the geminal ketones was most evident in the visible spectra,
Figure 27 through 29, which contain features not present in the
alkylated species. Following alkylation, changes on the substituents
of the pyrroline ring produced only small shifts in the visible
spectra due to the insulating effect of the reduced ring on the

residual conjugated system. Alkene formation, which extends

126.

Amm.ovmnm
Afio.ovoen

Ao.avunm
Ao.~vonn
Ao.~vuua

Amm.ovu:m
Awm.ovsmn
Aam.ovomn
Amu.ovomn

Amn.ovmon
Anm.ovoo:

“do.ovamn
A~m.ovnmn
Asu.ovmn:

Ao.avnmn
Ao.~vmo:
Ao.uv:mn
Ao.«vmnn

Ao.HVoN:
Ao.vao:

“c.avomn Add.ovnon

Awn.o.oo:
Amn.ovmo:
Auo.ova~n

Aofi.ovmo:
Auo.ovnoe
Aao.ovmm:
.no.ovc::

Amo.ovndn
Ano.ovn~m

Ao.~.~«:
Ao.«.umn

.o.fivnmm
Ao.dvfimn
Ao.~w~mn

.monogucogua =_ wagon o» o>wuo_oc m»=o_u_memoo =o_uu:_uxm me: e. zuo=m_m>cz a

.Nfi.o.«~n
Ao«.ovn~n
Amo.ov«nn

Aoo.ov:w:
Aoa.ovnm:
Aoo.ovoo:
Aoo.ovmo:

Aco.ovm:n
Ano.ova:n

A:~.o.o:m
Aod.ovaan
A:~.ovnmn

AnH.onm:
Aeo.ovo~w
An«.ovmm:
Ao~.ovmm:

AnH.ovnnn .ao.ovooo
Ano.oV~un Aao.ovnun

Amo.ovna:

Auo.o.om:
Aso.ov~m:
“no.ovfiaa

m:.g>gagoaogu»: coauo_om com can: _aguuoum u_=oguuo—m

Ao:.ovmmn Ano.ovamo
Amm.ovmmn Auo.ovmmo
Aua.ovmmo
Auo.ovwmo Aom.ovm~m
Aoo.ovoom Aom.ovmnm
Am:.ovo~m
Amm.ovomm
A-.o.~uo
Aon.ovumo
A:~.ovmno
Ao~.ovo~o
.nm.ov::o
.m~.o.o:c
A:~.ovnao

. aao~ cease

Ammv mamzo .zv
.mmv Nfinzu .zov
Amcv mxo .zo

.mCOumxocoe n.~

 

mcfluoHnoodmmpomnomH Hm:_Exu

Ammv «Ammo .zv

 

Ammv NAmzuv
mama»
mac
Amm. mAmzo .:ovo .m
Ava weepoxfic m .m
AmNV mcouoxan o .N
mcprH:90wumpomm HmCMEmc
Amwv ~=u
:N
i< mmmn monk
Ammv 3H modem .:
Ammv pmwoomzo .zo
ANN. nzo .=a
.mN. nzo .2

 

anamoano «zzpomuoo Adams»:
m c.aop

127.

700

 

 

 

 

“
“‘
I “‘
““|“
|“|
“"

500 600

400

 

 

 

moz<mmowm<

2:.)

of monoketone 66 (-—--)3

and methyl chlorin alcohol 77 (--

Electronic spectra

Figure 27.

~

 

 

128.

Moli

 

 

 

 

 

m

o

z

<

m

m

c:

a)

c:

<

f l l |
400 soo 600 700

Figure 28. Electronic spectra of 2.6 diketone 0 (

)
and alkylated products; mono alkylated (s---);
bis alkylated bacteriochlorin Q3 (....).

I

ABSORBANCE

 

129.

 

 

 

 

 

 

 

Figure 29.

Electronic spectra of 2.3 diketone 68 (
and alkylated products; mono alkylated iso-

bacteriochlorin

 

):

 

bacteriochlorin Z. (----).

130.

conjugation, results in an overall blue shift compared to the
alcohols. The elimination of diasteriomers also produces a narrowing
of peaks. .

The absorption spectra also revealed the instability of
bacteriochlorins, Figure 30, which shows the effect of subdued room
light on the chromophore, T 1/2 - 20 min. Attempts to regenerate the
chromophore by addition of reducing agents failed.

The similarity of band maxima and overall spectral features of
these geminal alkylated systems and naturally occurring chromophores
demonstrates the viability of using these compounds as models.

1H NMR

 

Although the visible spectra served useful in monitoring the
substitution of geminal alkylated hydroporphyrins, NMR was generally
used as structural proof. In addition, side chain modifications could
only be observed in the 1H NMR.

The'lfl NMR of geminal dialkylated hydroporphyrins are'generally
not complex due to the high degree of symmetry in these models. The
reduced ring current associated with saturation of peripheral double
bonds was most evident in the upfield shift of neighboring meso
hydrogens and the downfield shift of inner pyrrole hydrogens. In
chlor ‘ins, two methines are adjacent to a pyrroline ring and are
shifted upfield. All four methines are shifted in bacteriochlorins,
while isobacteriochlorins have the most complex pattern due to the
distribution of reduced rings.

The geminal ketones and exo-methylene compounds show a high degree

of symmetry corresponding to the rigidity and planarity of the

131.

 

   

 

 

ll ,
fl
| V “ nv
———-'
w "n .
W
15 I1
ll
2: l
‘
O
C
O
C)
O
(
~—‘__.__, -
360 460 560 660 700 360

Figure 30. Electronic spectra of reduced 2.6 bacterio-
chlorin Q3 (---—)3 and effect of exposure to

light ( ).

 

132.

partially reduced ring. Figure 31. The planarity of the
exo-methylene bacteriochlorin. 85. analogous to bacteriochlorophyll
b63, has been shown by x-ray analysis, Figure 32. and may be important
in the aggregation of these chromophores during photosynthetic
processes.4S

Alkylation of the ketone or reduction of the methylene generates
chiral centers which reduce the overall symmetry of the molecule. as
evidenced by the non equivalence of geminal ethyl groups. The
diastereotopic nature of cis and trans bacteriochlorin diols was
easily determined by NMR. Figure 33. The isolated isomers possessed
different spectra due to retnetion or destruction of symmetry
following alkylation. The addition of acid to the samples produced
the same protonated intermediates. which after work up yielded
identical alkenes.

Reduction of the alcohol or alkene was easily determined by the
appearance of the pyrroline hydrogen, ca. 8 3-4 ppm and the splitting
of the geminal alkyl substituent. The prochiral nature of the ethyl
hydroxy ester has already been discussed. The attachmeent of
imidazole side chains was easily determined by the appearance of
imidazole hydrogens. The integrity of these species was verified in
the same fashion as the diphenyl porphyrins. The addition of
trifluoroacetic acid results in coulombic repulsion of the protonated
species. Figure 34 and zinc incorporation causes coordination, Figure
35, both causing the expected changes in side chain and imidazole
hydrogen resonances.

The 1H NMR of the ligated species proved extremely concentration

dependent due to severe aggregation, Figure 36. In general, the

.Ammv :0 u .m .mzo u m Ame “Amws

mmo n A.m .mv A<v «mewmoanoownmpomn mamaznpme mo wepoomm msz rfi .Hm mmswflm

_N.. .u c. my my Au.

Pr*b_bbP>1—L*pPLPFh*L_Ft+ IPL—bbbLLl’blDt—VPLDb’_'bh>bh*LbbLbLthPbbb?

371....

 

 

L jjjjjjj

133.

 

 

 

 

 

 

 

 

 

nu..."-

 

 

 

«:0.

 

 

134.

 

Figure 32. ORTEP representation of 2.6 dimethylene bac-
teriochlorin Q2.

.mwo Amy .mcmup A<v “Ammv maosoodm Cahoago

nodumpomnachmmHoo ficfismm szmewc w.m owemEOHhmpmmHn e0 meuomam mzz xa .mm mezwflm

NI O N c m m o.

_bhbblprLpL—bDBL—bPIPb—bbrbbbb-bblbfs

slllll

J . i A .

tLL—bbilbib_bbrb—LbL-bit—VLLbbhlh-Dbl—thb‘

 

 

 

 

 

 

 

 

 

 

 

135.

 

 

 

 

 

 

 

 

 

 

 

136.

in

Homo :H Rev

.<me-maoao Amy

2

a m cfluoano newsmmgm maoumufisfl mo mppoomm mzz :

H

.:m wpswflm

137.

 

 

N

bhfibL-blbbb_bb.b|Di-bbb|D—|bbb

 

 

 

 

 

 

bl—rLLLIbl—LLL L b

 

 

 

 

 

 

 

 

m

 

 

 

 

o.

 

b‘ibl?$b$blbblrlbik— blbllbllbv

<

in .:N u 2 Amy .mm a E
.mme ompm A<v .sm Camoago Umqummm maoumquH mo mepommm mzz :fi .mm muswwm

I o N ¢ w m
N _tiLliTiLiCer

rbphrmbblPLr—mtrthLbbbPrbll—bmnanLrbbbbeP—bbbb

i q

 

 

 

 

 

 

138.

 

 

 

 

 

 

 

139.

 

 

 

 

'l—VT‘T’FIIIlfiVV. ‘

I if

e 7 e 5 PPM

Figure 36. 1H NMR spectra of appended chlorin 89 showing
affect of increasing dilution. lowest trace
most concentrated.

140.

overall features of spectra are more important than absolute chemical
shifts.
Eyelic Voltaue'tq

Cyclic voltammetric measurements reveal the redox potentials for
the reduced system and the effect of metal incorporation. The redox
properties of hydroporphyrins are important due to the possible redox
role of the macrocycle itself in multrelectron enzymatic reductions as
well as the role of cation radicals in photosynthetic systems.45 The
redox potentials of geminal alkylated hydroporphyrins are listed in
Table 9.

All free base porphyrins and hydroporphyrins exhibit the same
three step redox curve. but at distinctly different potentials. Figure
37. These include the successive formation of mono and dication
radicals at oxidizing potentials and the formation of a mono anion
radical at reducing potentials.

The oxidation potential for the formation of the mono cation
radical for geminal alkylated hydroporphyrins follows the same order
as other reduced series64; bacteriochlorin < isobacteriochlorin <
chlorin < porphyrin. The greater the degree of saturation, the easier

it is to abstract an electron from the Trsystem.
Dihydro and tetrahydro-porphyrins of TPP and OEP generally oxidize

at high potentials to more highly oxidized macrocyles.65 The geminal
alkylated hydroporphyrins are resitant to this dehydrogenation as
evidenced by the lack of decomposition even after numerous scans.

The effect of substituents on the pyrroline ring was generally
small, the alcohol, acetate, and methylene derivatives show little

shift in the chlorins, and only about 50 mV increase in oxidation

 

Table 9
0E?
Chloring
OH. CH3 (22)
H, CH3 (73)
CH2 (85)
Bacteriochlorins
2. 5 0H. CH
2. 6 on. CH (§})
H. CH3 (Q3)
CH2 (5;)
Isobacteriochlorins
2. 3 on. CH3 (23)
OAc. CH3
H. CH3 (89)
CH2 ~

Chlorin - Imidazole

free base (Q2)

Zinc

Tetraphenyl

TPP
TPC
Zn TPC
TPBC

a Spectra run in CH
electrolyte and S

141.

ringazring+

0Z1+ 1+[2+
0.83a

0.58 ----
0.57 1.18
0.58 1.19
0.59 1.18
0.33 1.01
0.30 0.97
0.30 0.96
0.26 0.97
0.32 1.03
0.38 1.02
0-37 0-95
0.33 0.92
0.38 1.02
0.56 1.16
0.30 0.76
1.06 1.35
0.88 1.17
0.28 0.92
0. 3 0.92

Cl2 using (Bu)u NClO

8E2 as reference nelec%r

ring - ring”

1.13

as the

ode.

Redox Characteristics of Hydroporphyrins

0(1-
-1.45

-1.45
-1.52
-1.50
-l.h7

-1.u3
‘10“6

-l.42

-1-53
-1.50

-1.46

-1.29
-l-33

-1.29

support ing

142.

 

 

 

 

 

Volts vs 805

r

I r I r T 1 V f l V Y I V I V V I V I Y I V

_ 'l . . l'
1.0 0.5 O ' 0.5 ' 1-0 ' 1.5

Figure 37. Cyclic voltammograms of gemini alk lated hy-
dropor hyrins derived from OEP; (A chlorin
8; (B isobacteriochlorin O; (C) bacterio-
c lorin 83. Spectra measure in CH C12 with
(Bu)4NClou as supporting electrolytg.

143.

potential for the reduced bacterio and isobacteriochlorins. Little
variations were also observed in the oxidation potential of
configurational'isomers. The 2.6 and 2,5 bacteriochlorins showed only
a 25 mv difference, the latter being more difficult to oxidize.

Zinc_incorporation increases electron density of the ring. making
it easier to oxidize. The free base of imidazole appended chlorins
was 250 mV more difficult to oxidize than the corresponding zinc
complex. A similar trend in the incorporation of zinc into
bacteriochlorins would produce a species which had an oxidation
potential of 0V. or less vs S.C.E. The metallated species would
easily photooxidize to the cation radical which may account for its
instability and the difficulty encountered in generating it.
Metal Insertion and Coordination Studies

The lower acidity of reduced porphyrins hinders the incorporation
of metals.52 Geminal alkylated chlorins and isobacteriochlorins can
be metallated by standard conditions using longer reaction times.
Similar treatment of unstabilized hydroporphyrins would lead to
partially dehydrogenated products. Efforts to insert metals into the
least acidic hydroporphyrin, bacteriochlorins, failed.

Bacteriochlorins of TPP have been metallated. however, no model
studying involving B-substituted bacteriochlorins has been reported.
Metallation of the naturally occurring bacteriopheophytin requires
special techniques and the yields are inevitably low.69 In nature the
metals are incorporated before the rings are reduced. Efforts to use

the zinc diketones in alkylation only produced demetallated diols.

144.

The inability to metallate these model bacteriochlorins limits their
study, however,_the free bases have provided information on the

structure and reactivity of bacteriochlorins.

The 02 and co binding constants for the imidazole appended ferrous
chlorins and isobacteriochlorins have been reported elsewhere.64d’8‘
Rates indicate that the presence of the fifth ligand, imidazole,
outweights any electronic effect due to the reduction of the ring
system.

The zinc derivatives of the tailed chlorins exhibit unusual epr
properties. The cation radical of the zinc complex exhibits two
signals at room temperature but only one at reduced temperature. As
the chain length was shortened. the temperature at which the two
signals coalesce rises. These observations imply the presence of two
species at room temperature and only one at reduced temperatures. The
two species may be either inter- and intra-molecularly bound species.
or two types of intramolecularly bound systems, Figure 38. As the
temperature was reduced. the more stable species was formed,
representing the intramolecularly bound species of least strain. More

detailed discussion of these results will appear elsewhere.66

 

Figure 38. Possible orientations for intramolecular' coordination
in the zinc complex of appended chlorin g2.

ABSORBANCE

 

 

145.

 

 

 

Figure 39.

 

l l l T
400 500 600 ' 700

Electronic spectra of the ferric chloride
complex of methyl octaethylchlorin 8 C - )3
effect of adding Et N or 25% aq. Na (----)3
effect of adding (Ba)4N0H (....).

 

146.

“mm geneanoaazpmmpoo
.23me mo Noam—.80 63.3.20 0.2.8.“ capocmmsmmag .Ho sapwoonm mzz :H .3 95m:

om om o ow... oe...
rrrr—L r.rbrfrbrbbbbu\\mfb

£08 min...
“2 as:

*LLPPl—[brbrfiPFrPhbr_Lrppbr***b1r*+

 

 

 

 

.206

147.

Ferric Hydroporphyrins, Alkaline Form
During the course 0f 02 and CO binding studies on iron

 

hydroporphyrins; it was observed that the base treatment of ferric
hydroporphyrin-type hemes produced a species which was dependent on
base strength. Dilute or concentrated hydroxide. triethylamine. and
tetrabutylammonium hydroxide all produced unique species. as evident
by the visible spectra, Figure 39. In addition. it was observed that
electrochemical oxidation produced the same species as aqueous
hydroxide. This behavior was reminiscent of hydroxide formation in
protected hemes. as ferrous hemes will react with oxygen to generate
ferric hydroxides. The ability of unhindered iron hydroporphyrins to
stabilize hydroxide formation was unexpected and may be important in
species which utilize iron hydroporphyrins and oxygen.

NMR analysis of ferric hydroporphyrins and other unprotected hemes
indicate that a transient alkaline form can be generated and the it is
of high symmetry. The existance of few studies on ferric hydropor-
phyrin-type hemes, due to their instability, make correlations
difficult.67 The spectra of these systems are generally complex and
assignments limited by the presence of diasteriosomers and magnetic
inequivalences. The 1H NMR of the ferric chloride form of methyl
geminal octaethylchlorin. 283 Figure 40, reveals the complex nature of’
reduced hemes.

Treatment of the ferric chloride with basic deuterium oxide
generated initially the alkaline form, Figures 41 and 42, which

gradually converted to the lJ-oxo dimer. This final form was

148.

 

 

 

 

 

 

 

 

 

 

 

T T l T T i T
-60 -50 -40 -30 -20 - I 0 0
Figure 41. 1H NMR spectra monitoring the addition and

reaction of ODf/D O to Fe(III)Cl com lex of
chlorin 29. (A) P§(111)c1. no base. B) 10

min after addition of base: (C) 20 min after
addition. complete conversion to alkaline form.

149 e

 

 

 

 

e w

 

 

 

 

 

 

 

 

b

. Limp,
T ' l V I l I I ‘
-8 -6 -4 -2 I)

Figure 42, Comparison of 1H NMR spectra of FE(III) com-
plexes of chlorin Z§i (A) chloride; (8) "alka-
line form"; (C) u—oxodimer.

 

b A)\ . ’
JUL 40, A.

150.

 

 

 

 

1m-

 

 

 

 

] T

 

r* r l r4‘fi r T
-40 --20 o 40 60
Figure 43. 1H NMR spectra monitoring the addition and

reaction of ODf/D O to Fe(III)C1 complex of
octaethylporphyri . (A) Fe(III)Cl. no base;
(B) 10 min after the addition of base; (C)
completion of reaction. p-oxo dimer.

151.

 

 

 

 

 

 

 

 

 

 

 

a 0 g
‘Vrl‘Vf‘lvavIvvv

'I'rj‘l'r"l‘"‘Tnf'ir'r'TT"fi
-30 -60 -40 -20 O

 

Figure 44. 1H NMR spectra monitoring the addition and
reaction of OD'/D 0 to Fe(III)C1 complex of
tetraphenyl porph rin. (A) Fe(III)Cl. no base;
(B) 10 min after addition of base; (C) comple-
tion of reaction. u-oxo dimer.

152.

 

 

 

 

JL—N W L49

b .JL_JKJW_A1
_JLMA _ N

1‘ Y'fjln" jvv‘lvf'YTY'Tjj'Tvifi"Yvivrnl""1"_
-so Jo --20 0 40 so

 

 

 

 

 

 

 

W

 

Figure 45, 1H NMR spectra_monitoring the addition and
reaction of ‘Dl/D 0 to Fe(III)Cl complex of
etioporphyrin. (£5 Fe(III)Cl. no base:

(B) 10 min after addition of base: (C) com-
pletion of reaction. u-oxo dimer.

153.

identical to that generated by elution through alumina. The high
symmetry of the alkaline and chloride forms was evidenced by the broad
singlet and shoulder corresponding to theixrmethylenes which appear as
a doublet in the p~oxodimer. The alkaline form was also characterized
by the low field resonances for the other ring substituents.

Similar treatment of OEP and TPP produced only the strongly
antiferromagnetically coupled p-oxo dimer. Figures 43 and 44. Etio
porphyrin. which is of lower symmetry. produced a transient species.
Figure 48. The high symmetry of this species was indicated by the
ring methyl resonances which appear as a doublet in the chloride form
and as a low field singlet in the alkaline form. The iJ-oxo dimer of
this porphyrin shows only meso hydrogens in the low field region.

The high symmetry of the alkaline form may be accounted for by
bis-hydroxy type species. or coordination of water as the sixth
ligand. Hydrogen bonding. Figure 46. can create an extremely

symmetric species.

H \0/ Ho...“ /H

Figure 46. Possible structure of highly symmetrical ferric
hydroxides.

154.

The reduced rates in p-oxo dimer formation for hydroporphyrin-
type hemes. may be attributed to the well documented increased
flexibility of the hydroporphyrin skeleton. Affinity for weak
ligands. e.9” "20. is strongly dependent on the flexibility of the
core in allowing the metal center to expand.68 Coordination of these
weak ligands reduces the availability of free binding sites which may
be necessary in 'J-oxo dimer formation.

Experimental
OEP Oxidation

Octaethyl porphyrin (1 gm) dissolved in sulfuric acid (100 ml) was
cooled to O‘C in an ice bath. Hydrogen peroxide (18 ml. 32) was added
dropwise at such a rate that the temperature did not exceed 15‘.

After completing the addition (ca. 15 min) the reaction was stirred 10
min further in the ice bath followed by‘lS min removed from the bath.
The reaction was then quenched by pouring into water (250 ml)
containing sodium acetate (100 gm).

The crude solid was collected by filtration and redissolved in
methylene chloride (500 ml). The solution was washed with water and
52 NaOH. separated. dried. and evaporated to dryness. The crude
product was chromatographed on a silica column 2 x 12 in (Baker 3405).
The first fraction was collected with hexane/CH2c12 (40:50) until the
eluent became green. The second fraction was eluted with 1002 CHZCIZ
until the eluent no longer appeared green.

The initial fraction was purified further on a series of columns

and plates to yield pure ketones which can be recrystallilzed from

155.

CH2C12/methanol. The mono ketone Q9 and 2. 6 diketone. 19. were best
separated using an activated alumina column with 1:1 hexane-Cflzc12,
The isomeric bacteriochlorins. 2.5 and 2.6 were separated by
fractional recrystallization. the 2.5 isomer. 11. was slightly more
soluble in methanol. The oxophlorin. 13. and unreacted
octaethylporphyrin. due to low solubility. tend to persist as small
impurities in all fractions. The 1.4 diketone. 92. which occurs in
the lowest yield due to steric congestion. was extremely difficult to
isolate from the 2,5 diketone. 13. To obtain the alkylated species it
was easiest to alkylate the mixture and separate the isomeric alcohols
which show a greater difference in retention rates than the ketones.

The second fraction contains the remaining two isobacteriochlorin
ketones and triketone impurities. The 2.4 diketone. El. were
separated from the triketone by a series of columns or plates.
Alternatively, if recrystallization from methylene chloride-methanol
was slow, the diketone plates can be manually separated from the
triketone needles. .Purification of the 2.3 diketone, E8, was
extremely difficult. if pure diketone was needed the best route was
degradation of the triketone impurities with methyl lithium.

All of the ketones isolated were characterized by visible and 1H
NMR spectra and correlated well with previously published values.58
Methylation of Ketones

The ketone was dissolved in ether or THF and treated with an
excess of methyllithium. After a few minutes the reaction mixture was

quenched with water. The organic layer was separated. dried, and

156.

evaporated to dryness. Purification was easily achieved using silica
columns in subdued light. Separation of diasteriomeric diols was
easily obtained but was unnecessary due to isomerization during
reduction.
Esthyl Gemini Octaethylchlorin Alcohol (13)

1H nun (CDC13)8-2.58(s. 2H. NH). O.71(t. 3H, CH3). 0.97(t. 3H.
CH3), 1.80(m. 18H. CH3). 2.10(s, 3H. CH3). 2.30(m. 2H. CH2). 2.60(m.
2H. CH2). 4.02(m. 12H. CH2). 6.52(s. 1H. 0H). 8.77(s. 1H. meso).
9.18(s. 1H. meso). 9.75(s, 1H. meso); Mass Spectrum (70 eV). 566 (M+).
calcd. 566.
2.6-Dimethyl Gemini Octaethylbacteriochlorin Biol (81)

Trans
1

 

H NMR (£0613) 8-2.31(s, 2H. NH). 0.88(t, 6H, CH3). 1.18(t. an, CH3),
1.74(t. 12H. CH3). 1.98(S. 6H. CH3). 2.1(m. 4H, CH2). 2.53(m, 4H.
CH2), 2.64(s, 2H. 0H). 3.85(m. 8H, CH2), 8.62(s. 2H. meso). 8.89(s,
2H. meso); Mass Spectrum (70 eV) 562 (M+). calcd. 598.
915
1H NMR (c0c13) 8-2.33(s, 2H, NH). 0.7S(t. 6H, CH3). 1.30(t. 6H,
CH3). 1.74(t, 12H, CH3). 1.87(S, 6H. CH3). 2.37-2.75(m. 8H, CH2).
3.83(m. 8H. CH2), 8.56(s. 2H. meso). 8.88(s. 2H, meso); Mass Spectrum
(70 eV) 562 (M+). calcd. 562.
2.3 Dimethyl Gemini Octaethyl Isobacteriochlorin Biol (13)
1H NMR (c0013) 80.86(t. 6H, CH3). 1.2m, 6H, CH3). 1.68(m. 12H.
CH3). 1.90(s. 6H. CH3), 2.48(m. 8H, CH2). 3.69(m. 8H. CH2). 5.70(s,
2H. OH). 7.12(s. 1H. meso). 7.31(s, 1H. meso), 7.33(s. 1H, meso).
8.52(s. 1H. meso). Mass Spectrum (70 ev) 598 (M+), calcd S98.

157.

‘Qggydration of Alcohols

The alcohol was dissolved in dry Cflzc12 containing triethylamine.
Methanesulfonyl chloride was added dropwise until the reaction was
judged complete by tlc. Hater was added and the organic layer
separated and washed successively with; 10! HCI. H20. and saturated

NGHC03. After drying the product was purified through a silica pad.

Alternatively. the chlorin and bacteriochlorin alcohols may be
eliminated by simply washing with strong acid. A methylene chloride
solution of the chlorin and bacteriochlorin required 252 and 151 HCI,
respectively.

Methylene Gemini Octaethylchlorin (8g)

1H NMR (00013) 5-2.50(s. 2H, NH). 0.36(t, 6H, CH3). 1.85(m. 18H.
CH3), 2.34(m. 2H, CH2), 2.70(m. 2H. CH2). 4.00(m, 12H, CH2). 5.65(s.
1H, vinyl H). 6.97(s. 1H. vinyl H). 8.80(s. 1H. meso). 9.50(s. 2H.
meso). 9.78(s. 2H. meso); Mass Spectrum (70 eV) 548 (M+). calcd. 548.
Z-Methylene-G-ol Geminal Octaethylbacteriochlorin (83)

1H ... (00013) 6-2.23(s. 2H, NH). -2.20(s, 1H, NH). 0.37(t. 6H, '
CH3). 0.8S(m, 3H, CH3). 1.29(t. 3H. CH3). 1.75(m, 12a, CH3). 1.94(s.
an. CH3), 2.0-2.7(m. 8H. CH2). 2.76(s, 1H, 0H). 3.88(m. 8H. CH2).
5.53(s. 1H. vinyl H). 6.80(s. 1H. vinyl H). 8.62(s, 2H. meso). 8.86(5,
1H. meso). 9.31(s. 1H. meso).

2.6 Dimethylene Gemini Octaethylbacteriochlorin (13)

1" "NR (60613) .S-z.20(s, 2H, NH). 0.35(t, 12H,-CH3). 1.77(m. 12H,
CH3). 2.24(m. 4H. CH2). 2.59(m, 4H. CH2). 3.87(m. 8H, C82). 5.59(s.
2H. vinyl H). 6.78(s. 2H, vinyl H), 8.60(s, 2H. meso). 9.27(s. 2H,
meso). Mass Spectrum (70 eV) 562 (M+). calcd 562.

158.

Reduction by HI-MPsoz-HOAc
Hydriodic acid (5 ml. 56.72) was cooled to 0’ in an ice bath.

glacial acetic acid (5 ml) was added dropwise. followed by
hypophosphorous acid (1 ml. 501). The solution should obtain a yellow
cast which gradually fades. The reagent should be stored at reduced
temperature and was effective for several days.

The methylene or alcohol (50 mg) was dissolved in acetic acid (20
ml) containing ascorbic acid (50 mg). An excess of the freshly
prepared reducing solution (0.5 ml) was added and the mixture warmed
to 60‘ for ca. 3-5 min. After cooling. the mixture was diluted with
water and extracted with cu2c12. The organic layer was separated and
washed with dilute base and water. dried and evaporated to dryness.
The products were purified through a silica gel column to yield the
reduced species. yield ca. 752.
Methyl Gemini Octaethyl Chlorin (18)

1H mm (c0013) 8-2.2(s, 2H, NH). 0.44m, 3H, CH3). 0.9m. 3H,
CH3), 1.78(m. 18H. CH3). 2.10(d. 3H. CH3). 2.48(m. 4H, CH2). 3.92lm.
12". CH2). 4.73(q. 1H. ring H). 8.71(5, 1H. meso). 8.87(s, 1H, meso).
9.69(s. 2H. meso); Mass Spectrum (70 eV) 551 (M+). calcd. 550.
2.3 Dimethyl Gemini Octaethyl Isobacteriochlorin (89)
1H NMR (coc13) So.72(t, 6H. CH3). 0.90(t. 6li, CH3). 1.42(m. 12H. CH3).
1.60“. 3H. CH3), 1.93(m. 8H. CH2). 3.26(m. 8H, CH2). 3.80(0. 2H. ring
M). 6.70(5. 1H. meso). 7.15(s. 2H. meso). 8.38(s. 1H. meso); Mass
Spectrum (70 eV) 566. calcd. 566.

159.

Diimide Reduction

The dimethylene and reduced bacteriochlorins were handled in the
dark due to their extreme instability to light. 2.6 Dimethylene
gemini octaethylbacteriochlorin, 83. (100 mg). tosyl hydrazide (66 mg)
and potassium carbonate (218 mg) were dissolved in pyridine (10 ml).
The mixture was purged of oxygen and heated with stirring to 105'C.
After two hours additional tosyl hydrazide (66 mg) was added. the
addition was repeated every two hours until the visible spectra
indicated completion of the reduction. After 17 hours the ratio of
reduced to methylene compounds was 7:1 according to the intensity of
the Sorets.

Upon completion of the reaction. benzene and water were added to
the mixture. The solution was then digested 1 h on a steam bath. then
cooled. The organic layer was separated‘and washed with 3H HC1.
water. and sat. bicarbonate. Concentration. chromatograph on a silica
gel column. and recrystallization from hexane/CH2“2 yields shiny
green flakes.
2,6-Dimethyl Gemini Octaethylbacteriochlorin (83)

1H NMR (c0c13) 8-2.25(s, 2H, NH). 0.590.941.73m. 12H, CH3).
1.99(t. 6H. CH3), 2.08-2.46(m. 8H, CH2). 3.82(q. 8H, CH2), 4.57(m. 2H
ring H). 8.52(s. 2H, meso). 8.67(s. 2H. meso). Mass Spectrum (70 eV)
566 (M+). calcd 566.

Lithium Aluminum Hydride Reduction of Ketones

The ketone was dissolved in dry THF and an excess of LiA1H4/THF

was added. The reaction was quenched by the slow addition of water.

.Alcohols.were.purifiedoon a silica gel pad.

160.

Hydro Gemini Octaethylchlorin Alcohol (89)

1H mm (coma) 8-2.57(s, 2H, NH). o.72(t, 3H, CH3), 0.96(t, 3H. CH3).

1.80(m, 18H, 0H5), 2.29(m. 2H. CH2). 2.57m, 3H. CH2. ring H). 3.88(III.
12". CH2). 6.52(s. 1H, on). 8.77(s. 1H, mesa). 9.18(s, 1H, meso),
9.75(s, 1H. meso). 9.76(s, 1H, meso); Mass Spectrum (70 eV) 562 (M+).
calcd 562.

Ethyl Acetate Gemini Octaethylchlorin Alcohol (81)

To freshly distilled hexane (5 ml) under argon and cooled to 0'
was added methyllithium (7.6 ml, 1.4 M) followed by diisopropylamine
(1.4 ml). The reaction mixture was allowed to warm to room
temperature and stirred 10 min further. The solvents were removed in
vacuo, producing a white, flakey solid. Dry THF (10 ml) was
introduced, after the lithium salts have dissolved the solution was
cooled to -78'. Ethyl acetate (0.97 ml) was added dropwise and the
mixture stirred for 5 min. A solution of monoketone, 63, (120 mg) in
THF (50 ml) was added through a cannula, and the mixture stirred 5 min
at -78° before allowing to warm to room temperature. After 10 min,
the reaction was quenched with saturated aqueous ammonium acetate.
The organic layers were separated, washed with water, and dried over
sodium sulfate. The alcohol was purified through a silica gel pad,
yield ca. 85:. 1H NMR (00013) 8-2.38(s, 2H, NH). 0.36(t, 3H, CH3),
0.59(t, 3H, CH3). 1.60(t, 3H, ester CH3). 1.80(m, 18H, CH3). 2.4(m.
1H. CH2), 2.67(m, 1H, CH2). 2.62(d. 1H, ester CH2). 3.09(m, 1H, CH2),

3.25(d, 1H, ester CH2). 3.68(m, 1H, CH2), 3.93(m, 12H, CH2). 6.22(5.
1H, 0H), 8.71(s, 1H, meso), 8.95(s, 1H, meso). 9.70(s, 1H, meso),

161.

9.72(s. 1H, meso); Mass Spectrum (70 eV). 638 (n+). calcd. 638.
IR(K8r) v20 1780.
Ethyl Acetate Gemini Octaethylchlorin, Reduced (89)

The chlorin alcohol 81 was reduced in the same manner as the
simple chlorin 77, yield. 80:. 1H NMR (c0c13) 8-2.46(s, 2H. NH),
0.40(t, 3H, CH3). 0.97(t, 3H, CH3). 1.40(t, 3H, ester CH3). 1.80(m.
18H. CH3). 2.15(m, 1H, CH2), 2.40(m, 2H, CH2). 2.65(m. 1H, CH2).
3.50(m, 2H, CH2). 3.7-4.1(m, 12H, CH2). 4.44(q. 2H, ester CH2).
5.29(t, 1H, ring H), 8.73(s, 1H, meso). 8.88(s, 1H, meso), 9.73(s, 2H,
meso); Mass Spectrum (70 eV) 622 (M+), calcd. 622; IR(K8r) co 1760.
Amide Linked Imidazole Chlorin (Q3)

The ester (30 mg) 88 was dissolved in CH2c12 (10 ml) and diluted
with methanol (20 ml). Methanolic sodium hydroxide (5 ml, 52) was
added and the mixture allowed to stand overnight.

The next day the solution was diluted with CHZCIZ and water, the
organic'layer separated and dried. The crude acid was dissolved in
dry cuzClz (20 ml) and refluxed with oxalyl chloride (1 ml). After 20
min, the solvent and excess oxalyl chloride were removed in vacuo.

The residue was redissolved in CHZCIZ (10 ml) and treated with
3-(H-imidazolyl)propylamine and refluxed 1 h. Extraction and
chromatography produced the tailed chlorin, yield 502. 1H NMR (CDC13)
-2.S(br s, 2H. NH). 0.67(t, 3H, CH3), 0.90(t, 3H, CH3). 1.75(m, 18H,
CH2). 2.0-2.8(m. 8H. CH2). 2.9-3.4(m, 6H. CH2). 3.9(m, 12H, CH2).
5.12(t, 1", ring H), S.51(t. 1H, NH), 6.21(s, 1H, Im-H), 6.56(s, 1H,
Im-H), 7.05(s. 1H, Im-H). 8.73(s, 1H, meso). 8.85(s. 1H, meso).

162.

9.67(s. 1H. meso). 9.69(s, 1H, meso); Mass Spectrum (70 eV) 702 (M+).
calcd 702.
3-(1-Imidazolyl)propylamine

Acrylonitrile (20 gm. 0.38 mol) was heated to 75'C and imidazole
(13.6 gm, 0.2 mol) was added in small portions. The mixture was
heated to 90‘ and stirred for 3 h. After cooling, the mixture was
evaporated to dryness and the residual oil dissolved in methanol (100
ml). The solution was decolorized with activated charcoal, and
concentrated to yield the 1-(B-cyanoethyl)imidazole.

The nitrile (18 gm), dissolved in methanol saturated with ammonia,
was hydrogenated with H-7 Raney-nickel catalyst (50 psi) for 4 h. The
solution was flushed with nitrogen and filtered. Treatment with
activated charcoal and concentration produced a sticky yellow oil.

The oil was purified by bulb to bulb distillation (200‘, 4 mm Hg) to
yield a colorless oil. 1:1 NMR (00013) 62.03(q, 2H, 012). 3.07(t. 2H.
CH2), 4.05(t. 2H, CH2), 6.80(s, 1H, Im-H). 6.94(s, 1H, Im-H), 7.4S(s,
1H, Im-H); Mass Spectrum (70 ev). 126 (M+). calcd 125. '
Ethanol Gemini Octaethylchlorin (21)

The ester chlorin, 88, was dissolved in THF and treated with an
excess of lithium aluminum hydride/THF. After 3 min the reaction was
quenched by the careful addition of water. Extraction with CH2c12 arm:
chromatography through a silica pad produced the corresponding alcohol
in >90: yields. 1H NMR (00013) 8-2.40(s, 2H, NH), 0.61(t, 3H, CH3),
0.83(s, 3H, CH3). 1.79(m, 18H. CH3). 2.22(m. 2H, CH2). 2.56(m, 2H.
CH2). 2.72(q. 2H, CH2), 3.95(m, 14H, CH2). 4.72(t, 1H, ring H).

163.

8.70(s. 1H. meso)‘. 8.95(s. 1H, meso), 9.70(s, 2H, meso); Mass spectrum
(70 ev) 580 (me), calcd. 580.
Ester linked imidazole chlorins

The chlorin alcohol 21 was dissolved in CHZClz and treated with an
excess of the imidazole-acid chlorides. The mixture was refluxed for
2 h, diluted with water. extracted with CH2c12 and washed with dilute
acid, base, and water. Chromatography on thick layer silica gel

plates (5%.nethanolICH2c12) produced the tailed chlorins in high
yields (70-802). The products were recrystallized from

methanol/CHZCIZ to yield shiny green flakes.

Ester Linked Imidazole Chlorins, n31 (23)

1H NMR (c0013) 5-2.40(s, 2H, NH), 0.75(t, 3H, CH3), 0.80(t, 3H, CH3).

1.83(m, 18H, CH3). 2.12(m, 2H, CH2). 2.32(m. 2H, cuz). 2.50(m. 2H.
CH2), 2.70m, 2H, CH2), 3.95m, 12H, CH2). 4.56(s, 2H, 082m), 4.60(m,
3H, ring H, CHZO). 6.84(s, 1H. Im-H). 7.08(s, 1H. Im-H). 7.43(s, 1H,
Im-H), 8.71(s, 1H, meso). 8.87(s, 1H, meso). 9.70(s, 2H, meso); Mass
Spectrum (70 eV). 688 (M+). calcd. 688.
_n_=_2_ (33)

1H NMR (60013) £-2.42(s, 2H, NH). 0.63(t, 3H, CH3). 0.81(t, 3H,
CH3). 1.77(m. 18H. CH3). 2.23(m. 2H. CH2). 2.56(m. 2H, CH2). 2.71(m.
4H. CH2), 3.96(m, 12H, CH2), 4.15(t, 2H, CHZIm), 4.54(m, 3H, 0820,
ring H). 6.8S(s, 1H, Im-H). 7.00(s, 1H, Im-H). 7.48(s, 1H, Im-H).
8.68(s, 1H, meso), 8.87(s, 1H, meso). 9.70(s, 2H, meso); Mass Spectrunl
(70 eV). 702 (M+), calcd. 702.

£13. (23)

164.

1H NMR (coc13) 8-2.41(s, 2H, NH). 0.65(t, 3H, CH3). 0.82(t. 3H,
CH3), 1.80(m. 18H, CH3), 1.96(m. 4H, CH2), 2.20:. 4H, cuz). 2.570.,
2“, CH2). 2.76(m, 2H, CH2). 3.94(m. 14H, CH2). 4.6(m, 3". ring 3.
CHZIm). 6.80(s. 1H, Im-H). 7.03(s, 1H, Im-H). 7.43(s, 1H, Im-H).
8.70(s, 1H, meso), 8.89(s, 1H. meso). 9.70(s, 2H, meso); Mass Spectrum
(70 eV). 716 (M+). calcd. 716.
gzmgthyl,4-keto Gemini Octaethylisobacteriochlorin Alcohol (23)

Methyllithium (1.6 M ether) was added dropwise at room temperature
to a THF solution of 2,3 diketone 2} (50 mg). The reaction was
monitored by tlc, the mono alkylated species appears blue-green and
was of intermediate polarity. The red diol was the most polar species
formed. The reaction was quenched with saturated aqueous ammonium
acetate after a statistical distribution of the alkylated products
were observed. Ether extraction and separation on a silica gel column
produced the mono alkylated species, with yields dependent on
triketone impurities. 1H NMR (c0013) 80.50(t, 6H, CH3). 0.86(t. 3H.
CH3), 1.27(t, 3H, CH3), 1.68(m, 12H, CH3). l.90(s, 3H, CH3). 2.48(m,
8H, CH2). 2.70(s, 1H, Oh). 3.69(m, 8H, CH2). 8.09(5, 1H, meso).
8.31(s, 1H, meso). 8.43(s. 1H, meso). 9.23(s, 1H, meso).
‘gzggghyl, 4-Ethyl Acetate Gemini Octaethylisobacteriochlorin Diol (2E)

The mono alkylated IBC 25 was alkylated in the same fashion as the
monoketone 93 with LiCHZCOZEt. In NMR (c0013) 80.61(t. 3H, CH3).
0.89(t, 3H, CH3), 0.96(t, 3H, ester CH3). 1.04(t. 3H, CH3). 1.34(t,
3H, CH3). 1.48(m, 12H, CH3). 1.88(s, 3H, CH3). 2.14(m, 6H, CH3).
2.53(d. 1H. ester CH2), 2.91(d. 1H, ester CH2). 3.31(t. 3H, CH3).

165.

3.91(m, 1H. CH2). 4.07(m, 1H. CH2). 5.71(s. 1H, 0H). 7.11(s. 1H.
meso). 7.30(s, 1H. meso). 7.32(s. 1H. meso). 8.49(s. 1H. meso); Mass
Spectrum (70 er). 670 (M+). calcd. 670.
3-MethylL 4-Ethyl Acetate, Gemini OEIBC, Reduced

The isobacteriochlorin diol 2§ was reduced by the usual procedure
using the hydriodic acid reagent.

Mono Alcohol (98)
~

1
H NMR (coc13) $0.59(t. 3H. CH3), 0.85(t. 3H, CH3), 0.93(t. 6H, CH3).

1.35(t, 3H, CH3). 1.49(m. 12H, CH3). 1.67(d, 3H, CH3). 2.0(m. 8H.
CH2), 2.50(d. 1H, ester CH2), 2.92(d, 1H, ester CH2). 3.29(m. 8H.
CH2). 3.9(m, 3H, CH2. ring H), 5.73(s. 1H, 0H), 6.86(s, 1H. meso).
7.19(s, 1H, meso), 7.21(s, 1H, meso), 8.43(s. 1H, meso); Mass Spectrum
(70 eV). 654 (M+). calcd. 654.

3-Methyl 4-Ethanol Gemini OEIBC (£29)

The isobacteriochlorin ester. 22, was reduced by lithium aluminum
hydride in the same manner as the chlorin ester, 2g, to yield the
corresponding primary alcohol. 1H NMR (C0613) .So.55(t, 3H, CH3).
0.90(m, 6H, CH3). 1.30(t. 3H, CH3). 1.40(m, 12H, CH3). 1.63(d, 3H.
CH3). 1.70-2.5(m, 5H, 0H, CH2). 3.20(m. 8H, CH2). 3.70(m, 3H, ring H,
CH2). 6.94(s, 1H. meso). 7.08(s, 1H, meso). 7.17(s, 1H. meso). 8.33(s,
1H. meso).

Ester-linded Imidazole Geminal Isobacteriochlorin (£92)

The isobacteriochlorin alcohol, £29, was dissolved in CHZCIZ and.
treated with an excess of (ii-imidazolyl) propionyl chloride dissolved

in acetonitrile. The mixture was refluxed 2 h under argon then

 

166.

diluted with water. Separation of the organic layer and washing with

acid and base produced the crude product. Purification was performed

on thick layer silica gel plates (52 methanol/CHZCIZ). 1H NMR (CDC13)
0.50(t. 3H. CH3), 0.78(m, 6H. CH3). 1.22(t, 3H, CH3). 1.40(m. 12H,
CH3). 1.63(d, 3H, CH3), 1.8-2.5(m, 4H, CH2). 3.2(m. 8H, CH2). 3.70(t.
2H, CHZO). 3.80(t. 2H. CHZIm), 3.91(m, 1H, ring H). 6.47(s, 1H, Im-H),
6.57(s. 1H. Im-H), 6.83(s, 1H, meso). 6.85(s. 1H. meso). 7.15(s. 1H,
meso), 7.21(s. 1H. meso). 8.35(s, 1H, meso). Mass Spectrum (70 eV).
718 (M+). calcd. 718.

2-(N-Imidazolyl)acetyl Chloride

 

Ethyl bromoacetate (16 mg, 100 mmol) was slowly added to an
acetone (100 ml) solution of imidazole (6.8 gm. 100 mmol) containing
sodium carbonate (10.6 gm, 100 mmol). The reaction, which was
initially vigorous, was refluxed for 4 h. After cooling. the salts
were filtered off, and the solvent and excess bromo ester removed in
vacuo. 'The crude oil was dissolved in CHZCI2 and washed with water
and saturated aqueous sodium bicarbonate. After drying the crude
solid was recrystallized from hexane/CHZCIZ.

The ester (1 gm) was dissolved in acetic acid (20 ml) containing
hydrochloric acid (1 ml). After refluxing under argon for 1 h, the
solvent was removed in vacuo to yield the crude acid.

The crude acid was dissolved in acetonitrile and purged of oxygen.
Excess oxalyl chloride was added and the mixture refluxed until the
evolution of $02 ceased, ca. 1 h. Removal of excess oxalyl chloride

_and solvents on the pump produced an off white solid which was used

167.

without further purification. Ester; 1" NMR (60613) $1.56(t. 3".
C33), 4.44(q, 2H! CH2), 4.90(s, 2H. CH2), 7.13(s, 1H, Im-H). 7.23(s,
1H. Im-H). 7.66(s. 1H, Im—H); Mass Spectrum (70 eV). 154 (M+). calcd.
154.
3-(N-Imidazolyl) Proprionic Acid

Imidazole (6.8 gm, 0.1 mmol) and excess methyl acrylate (17.2 gm,
0.2 mmol) were dissolved in ether (50 ml). The mixture was refluxed
for 3 h. The excess acrylate and ether were removed in vacuo to yield
a yellow oil. Unreacted imidazole was removed by cooling the sample

and filtering. The acid and acid chloride were formed in the same

manner as the acetic acid analogue. 1

H NMR(CDCI3) 82.79(t, 2H, CH2).
3.70(s, 3H, OCH3), 4.28(t, 2H, CH2), 6.92(s, 1H. Im-H). 7.03(s, 1H,
Im-H), 7.50(s, 1H, Im-H); Mass Spectrum acid (70 eV). 140 (M+).
calcd. 140.

4-(N-Imidazolyl) Butyric Acid

 

4-8romobutyronitrile (8.3 gm, 51 mmol) and excess sodium
imidazolate (8.9 gm, 100 mmol) were dissolved in dry THF under argon:
The mixture was stirred 84 h at room temperature. The salts were
filtered and a yellow oil resulted after evaporation.

The crude imidazolyl .butyronitrile was added to a saturated aqueos
potassium hydroxide solution (16 gm, 6 ml H20). Enough ethanol was
added to obtain a homogeneous solution, and the mixture refluxed for s
h. After cooling to room temperature, HBr (482) was added drapwise
until a pH of 4 was obtained. The salts were filtered off and the

filtrate evaporated to yield a sticky yellow solid. The acid was

168.

washed several times with methanol to finally yield a yellow solid
containing a small amount of KBr.

The acid chloride was generated in the same fashion as the acetic
acid derivative. 1H NMR (coc13) 81.62(m. 2H, CH2). 1.80mi. 2H. CH2).
3-70(t.‘2H. CHZ). 6.68(s. 1H. Im-H), 6.81(s, 1H. Im-H), 7.34(s, 1H,
Im-H); Mass Spectrum (70 eV). 154 (M+). calcd. 154.

Hittig Reaction on Chlorin Ketones

Triphenylphosphine (36.2 gm, 0.14 mol) and ethyl B-bromo
proprionate (25 gm, 0.14 mol) were heated on a steam bath under
nitrogen for 1 h. After cooling the crude salt was recrystallized
from chloroform-ethanol. 20-1, diluted with ether.

A portion of the dry phosphonium salt (32 mg, 0.072 mmol) and zinc
monoketone §§ (30 mg, 0.049 mmol) were dissolved in THF-DHSO (15 ml,
1-1). The solution was added to dry sodium hydride (20 mg, 0.8 mmol)
under nitrogen at 0'8. After stirring for 1 h, the solution was
allowed to warm to room temperature and stirred 19.h further.

Dilution with water was followed by extraction with CHZCIZ. The
organic layer was separated, washed with 15% H01, H20, and sat.
aqueous NaHCO3. dried and evaporated to dryness. The crude product
was purified on thick layer alumina plates, 12 MeOH/CH2812. The third
major band corresponds to the desired chlorin 90, yield ca. 10:. 1H
NMR (coc13)S-2.50(s, 2H, pyrrole NH). 0.38(t, 3H, Me).

0.86(m, 2H, -CH2). 1.80(m, 24H, Me). 2.72(q. 2H, OCHZ), 4.0(m, 16H,
CH2), 6.80(s, 1H, CH). 9.04(s, 1H, meso). 9.81(s, 2H, meso). 9.98(s,

1H. meso).

. APPENDIX

169.

-Humammci.~.~-Haepe2me-.n.m-az:pemei.e.e mo asteoeem msz 2H ems ow

. ANV mqmnpma
.H< enemHm

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Si 5 an a. 1.2.: an ca 2
C — fl ‘ ‘ q _ ‘ ‘ ‘ q — ‘ ‘ q ‘ ‘ i d C _ d C ‘ T— I Q 1 4 _J 4
_ _ _ u m .
. _ r .n . _ _ e e
_ W m _ m _ _ m n _ _
u . . tinffiil. ) .1»). 11)) in)
L- . _(41 i. .11 6. 44). t l)
_ i. n F .
. . . . .
_ _ 4 _ n
m . _ ‘_ H
_ _ n . m .
_z: a . . Z . .i .-.... _ ”1.. ... .i m ...... . m
u.... . .-
_ _ m _ _. . ._ w)
_ . .............. H .....
n _ .. H _ ._ a z
" ... .
. _ H _ m .. z
_ H m u _ ..
_, . u _
. _ . ......m: ._ ; _ ...... / \ / \ .
fl ._, ,
H 13.. H . _ _ _
_ .___.e_ . . e H. _e 1
v. . :. _. I” J. . a; .
. _ .. _h . a. . _ .. M _ _ _
: . _.
. n 3;.” ..... _ _

170

.Cmmocfluzzapomofipm
maoncpmcv Any .Aev mmaoncpmcv Amv me empeegm mzz mm mm: 0mm .~< mmzmfie

N: o N a o m 0H
)F*)P)PP(PhLnleyb>h¥F>thP>fih>~bbbb—beLLLLFP—bb >LP>L,LFL»LLb>>»LFFLL>>1"rL>>

4 4.433% l . Q2. J8.

fiJWJxe

z =
25:25 «ox = a x z~o
x :

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

171

.mmo .mmnmfieemamuememmocm-sv Any
:3 m3 .mmfieflamncenmmoumiev.3:23 23 mo «38%,... 6‘2 5 am: omm .9 83mg

N a o m 3
.-_+-_._-.».e..)ip._,.e-.i .--)e.rP.L)-_.

h h P ' .7 '

 

 

 

 

 

 

 

 

 

 

 

172

.va 98 E .
.Anv madam Amy .mmnamcaemNConmmoaHisv. Aocwamv mo mmpoonm msz ma xxx own .34 mm:m«m

o N 3 c m ca

LLbhx—N‘Dbpbhb :—IP>P_IDPL -+bhb—LLbL—DPLbhbbbthhbbbLhbbhb>rrr—Pbbh—rbh

 

 

 

 

 

 

 

' L‘ ’ ‘1’
.I}($T)-l.ill -1.)J
_

 

 

 

 

 

 

 

 

173

 

 

 

 

 

 

 

. e LE F

4 d

 

q++411fl111141++4 <fififi1fiq++j<q4dfl4fl*<4fifi4 1*)1fidlqlui1‘

3 m o . ... N
wpmcnm >m. mmo 3mm Hx 23w mvmoanm om AaiHaommdmsumawamvmcwm. Amv owm Awmv. Adv «Hmbm Awwv.

174

.An~v mammp .mmoNAmoaemumomv mo sappummm as: :H mm: 0mm .w< mummfim

N a o m OH

I
++L1Pfibrrphrbp—VLIP*PLP)rr+)PFP+LIP)P r)?>rbrrlpbbrx—(LP>+PLI

J. . 443

 

 

 

 

 

 

175

N ~. 2 n 2.38 23.3 .me
Azzoumm :oVeHv Aev .Aoav agate .meomfimzoo AmmoveH. Rev “ABHV wedge .meamfimz

-oomz AmmuveHv Adv .xm u z .mmo eczema ahead amp mo «apogee msz :H um: omm .e< ecsmmm
H
1_C:m.:LI,L..C[_L,prliL..Cmiifibtl

 

1t!)
‘1 ‘I 1

0

 

 

 

 

 

 

 

11.

176

2 . m3. 22» .mmomgzoonfimzo: .5302 m:
,Amav meat» .mmnmfixzoo Ammovcmv Adv mo eaeoeem msz :H u:= omm .m< euzmmm

Ni o N a o m o."

— — .
Fr)*D(P})i?.P Dr)r>_rFIiPLPL P)D}(P)PLlPP*).>1—r>rb+b+**PPPrL>F+f$+b¥¥[b}’>F—?>?br

 

 

 

 

4. A 3. fifl fie-
37 a; 7...

«e

 

 

 

 

 

 

 

 

 

 

177

2
.AHNV usage .mmawfimcmemncenmxomozzisv mo espaommm :22 :H um: onw .m< emzmmm
w a o m 3
F)L.LF»)L>b>>>f—>L>L_))>»P)).+hpiiib)»»)b))>.~i

 

 

 

 

 

 

 

 

 

 

 

 

 

 

in m 2:
.0: u m Adv .mCmmocfimmnnuoa owaocmnn mo mmpomnm mzz ta um: onN .oa< mm3m«h

b )P (P L lb b L LP DL 1—7 L L L L, (- Ll» fi F + h b

 

 

 

‘1

J

 

 

 

178

 

. 4 i

 

 

 

 

 

179

.323 3E» .mmawaxocozé me 563%.... «:2 ma 3.: onm 42 9:58

N a o m 3

rPbyplPLbr¥|PrPLPL1PerlbrLLPFPLPblpbbrPbbbLLthrblpxp‘PiPlrpipfifiL

 

 

 

 

 

 

 

 

 

 

 

 

 

180

 

.Ammv emu .mmomflsxetezev mo esteeeam mzz ma ex: omN .~H< ecstm

N :

1—1Lr***l_)Pl.PL*LP(PLIP)PF**LPbePbLLNbLPIPlP_LbbL

Q Ca

hLleibx—bbbL-LL

. . l a.

 

 

 

 

 

 

 

 

 

181

o

bbbhfi_bbLhPLDbF—bbPL_bbLL_PbP*_#r*LWLPDLl—erL Lbrbe-Phbbl—rlrhbrp

 

 

 

.Ame mean» .mmouamvmoummnimmpiav no samuommm mzz xa ax: onm

 

 

 

’

.nac ecsmme

o“

%

182

z

.Ammv mm u s .mcaa» .mmawfiepmoscenmxosH-ev mo esceoeem msz mm mm: omm .eH< ecsmme

m e o m cm

bb_bbbL)—LLL)b)—ybbbb—rb+b)—bDPPL—bthrbLLFLLbLb_LPbbb—bL

 

 

 

 

 

 

 

 

 

 

183

.Amwv mama» .mmnamcfismucepismuinv.vaHemNCmpmxomo<iev any “Ammv menu»
.mmnaooaamscmnimmvinv.Aocaemnmmnmmommiev Amy mo mmpomgm mzz zH um: omN .ma< mmsmfim

o N a. o m om

’L; .- b ’» I _ D I F ’b D ’rL rrbLP>> P‘Lr*’L p p)’ bwhlrp.’ *biLr PL D ’ (p b Pp P’ h b b ’

J 4 1% J. 3....
., i .7 A???

 

 

 

 

 

 

 

 

 

 

184

.<ma + maoao Any .naoao any cm Aemv
mammv .mmaamoaamumonmxoeH av. Aouaemscopi :mvinv no mmwoomm mzz :H mm: omw

.v m. m

 

.QH< ecsmHm

nu.

*Ph5+»?W*‘*FL—f¥brb_>*rrip>irbyh)—11P*LbrpbL*+bL¥'Lp+L**hL*b

 

332$

 

 

 

 

 

 

 

w
4..

185

 

.Ammv meat» .mmaaxzoonANzoveHv.Aeemeancenieme-qvAny .Ammv meme»
.mmoaxzoomfl~:oveHv.Aeemsanceniamp-av any we emeoegm mzz za um: omm .nae ecsmme

m 3 o
_p.»i_l.L.L...i_Ll.i_L_i._-»r+F-

DD

 

 

3:

 

 

 

 

Q Ca

 

186

. Ann/WV wrap»
.mmaaxzooxznfiwxovsHv.Aoememucepismeiav mo espeeeem msz ma ax: omm .ma4 otewmm

m a e m cm

 

 

 

 

 

 

 

 

187

.Ammv an n e Ape .Ammv =m-e u m “as

.mmnaecmaaucep~:oeHisv coxooap mean» we ecpoegm mzz ma umzomu .ma< egaMmm
m a c m 3
P) »)L)»»)pr+LL.+)+L)+)p_»»»LEL))»P+L)>~»LL)_L»

 

 

 

 

 

 

.31 a
491 4.

 

 

 

 

188

.Ammv meet» .maerumeaueep
-mxoeHiev.Acumeaueonmasmc-xzoovn.mV me eeueoeam msz :H «x: onm .o~< emswmm

N a o m CH
LFLF h h (P Db . — bi F b b (—L b L b _I.’ ’ b h by F F )P P b (P b * ‘ bL F b P by ’ F

 

 

 

 

 

 

189

2 \I..
.Annv an n m Any .Aomv tam u m Amy .mmo
AocwamuconmzueHiev cmxooan modemNCmn mcmMp mo mmpomnm mzz ma um: onN .HN< mmswwm

o m a o m cm

.(Pb ’ ’ ’P’?'7-blr)r>b >)[bb)’>~b)r¥h*))' _)))l’ h 1|) ' _)>)Lb’)[b 9 D

j . . fin
ii/x . _ ...e

 

 

 

 

 

 

 

 

 

 

190

.Aenv meet» .mmafieemeeucen
immoEHisv.onfismummnmfismcimoovm .nv no sampomam mzz :H mm: onm .NN< mmswfim

N a c
. .Llplr1,+ . p... - . _. l ,.,_l+ _

h b * h I 1' ’ ’ h b > ’ _

33732.3

 

 

 

 

1'

fi

 

m o”
p

h b by h _L h D b b 1

£43.14

b D F

 

L

a

 

 

 

 

191

AM? new: 5833.3
-ueenmxoeHiev.Aeemeaucepmfixommovn.mv mo eeeeeeam «:2 ma um: omm .m~< ecsmmm

m a o m 3
eiiil_+)++_+i-,e,)+rkii-__

‘ b (P D h (P b ’ (FL I *LyLrLP+ r by ’ b ’L p ’

252.47

 

 

 

 

 

 

 

 

 

 

:0

192

.nmmv mcmhp .mmnAmcwEmscmn
-mxosaiav.AeemaaueenmAesomzovm.nv mo azupoeem «:2 ma um: emu .:~¢ enamHm

m a o m 3
Lib.iii.r.»)~i.i.h»)»tbiiit_iriiLp».i_

 

 

 

 

 

 

 

 

.<me + naooo Anv .naoao Adv cm «Ammv meme» .mmaaeemea

incopmzueHiev.Aeemeaseonwxomezz-ev mo amputee mzz ma «:2 omm .m~< ecsmmm
~ om
))»)L)>P»Lp)h)>.»W»>)»_L).>W>rr>pkir)mirripirr)h)>>

 

193

 

 

3.121 a
/ /

/
\ ,,<

 

 

 

 

 

 

194

.Amv ash». .NAHQAwUHEflN—MQQ
-mxoeHiev.Aeemeaucopmxomesz-ev mo seepeeem «:2 ma ax: onm .omc Guzman

. Ni o N .z o m o."
yrLblPrbi—rbrLbeILPbk—LLFL_F¥bbFfibLF_brIPbLbLFb*l_r>>bF—rrb>h_

’FLbl—bp’bhb‘LLLLibb

3 2.: 1.

 

(I)

 

 

 

 

 

 

 

 

 

 

195

.Ammv meat» .mmofieemee
-ucepwzoeH-ev.Aeememscenmxompmz-ev mo espeoeqm ms: xa um: onm .ema eusmme

Ni o N a o m CH

r+’L+b?lbrbrlr} PLD>LLP)*LF?P++F¥V*+rL*L**_fiLFLPL»??—Pr+b1PDhr7>->*”PFPD

: L a.

 

 

 

 

 

 

 

 

 

 

196

.Aeev emu Aev .Ammv meets Amy
.mmofioemseucenmzoeH-ev.Aeemeaeeoev mo eceoeae mzz :H um: omm .m~< euzwme

m e o m o«
ribpiiibpii)hii)._)++ipiiiipipiie.).ipititFiiirb)»

Jm

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

197

.mM man movemnnm

odoumvaefi .vmxooan ocwemcoams mo esmpowmm msz :H mm: omN

Ni 0

'Lt)? F b! r 7 ’ .br _7 r p by PF? p‘ * bL * > >L

(IJj

2

 

.m~< euzwmm

 

 

 

 

 

198

.mm man omchqqm
mHosmcwafl .vmxooan mcHEmCOHmsimm» mo emupomnm mzz xH um: onN .on< mummHm

o N a 0 m 0H

J)

 

 

 

 

 

 

 

199

.M$ man cmchnam
oaosmcwaa .voxooan «caemCOHma thvoeHv mo asmvomam msz xH um: omN .Hn< mmswwm

o N . a e . m CH

J] D

 

 

 

 

 

 

 

 

 

200

z
.Amzv mac .choagoowpm moNAocHsmv no esmpomam mzz ma um: owN .Nn< mmswfim

Ni o N d o m CH
.r»1-,.»il.-_,L»,»r.+i»..--»,...eiliiriiulr,-i,»,»i.».+L-e-,+,e-ii-»+,-

)) I?

 

 

 

 

 

 

 

 

 

 

201

 

 

 

 

 

 

 

"a
\_ .*H
an '43
0 ~
2
4
m
K
O
8
< )1
1‘2
U—U U 1 U 1 I l I I I ' V I 8
460 500 660 700
Figure A33. Electronic spectrum of (amino)2DP etio-

chlorin. cis (38).

202

.mean» .mmafixzoouammoveHv.Academy mo escpoeam mzz mm mm: onm .em< ecsmme

m- o m e

m 0H

FLLFLb)iPPppp_bbrhbbPPpr)>brLbPhPprbbbphrbRPLLLbbbbrebbberbLer)Pbbbbrb

In)

 

+

 

 

 

 

fin

 

 

203

.Ammv N u c any .Ammv n u a any .mmo «Honmumea

 

 

 

 

 

 

 

 

 

 

oeeeoana magma no moxemaeoe HomAHHHVem an» no ateeoem «22 :H ex: emu .mm< ec=Mme
ow o: o~ om- oz- om-
)i».))ip-i)_i-)>~)iiib)i)i -bii»»_ii.ib->L-LL L»-

--- l. .. i -- a
[1) ii 5 ii) ‘

mmt.hm

N

_wmw muvde.

 

 

 

 

204

.mm mmo eepoeeocm
amazon no weanaoo ooeHmAHHVem as» me esteoeem msz ma em: onm

 

 

 

 

.cn¢ mummHm
o N . e w m
)p--))—ii-)-))ilb ),)L))» hii))P)rL)L> i)_))- pi») F>)i>
ii ...]
2
§ \000
. I.
g I...
.... 0
\

 

205

i

’

.-

 

rL

'7

.mm mac vwvcoanm
odoumvwaa mo onQEOo ooaHmaHHvom map mo asapommm m2: ma mzs onN

N 3 o
b

_ ... _ b L h
k?) >)*) *b DLFI’ lelPP )>b+)>r’b

 

 

 

 

L

L

.un< etsmmm

OH

_
P i— ) L )i) . )

\lllll

206

z
.AeNV eme-e u m Amy .Ammv Nzoem-e u m Aav .mma eeeeaaee
eaosmemam mo eexoaeeee ooeHmAHHvem esp mo etpomam mzz ma am: can .mm< mesmMm

p m a w m ca

b 9 9* )P FLIP). (*Lrb .D 7 D b b1—I h D PP P rP D - h thb b)

3 (iiiiiigxiiiii. a

I p .L b F I l h > ’ ’ F

 

 

a

. <

 

 

 

 

 

 

 

 

 

207

 

 

. Levee
-2 AA

 

 

JL JLN

 

 

i; JR,“ M t) + on.

 

 

 

 

 

 

J ) fl ,1 ML” FePCl

 

 

‘6l0 T «'0 l - 2‘0 I 6 I

Figure A39. 1H NMR spectra monitoring the conversion of
Fe(III)PCl to Fe(III)POH in DPE 19.

208

 

6.|
‘ 2.o

 

 

 

 

 

 

‘— W
l 1 I I l 1 I Y I l I T U ‘ 1— U T I ‘ l I T U
I - 2 3 44 KG;

Figure A40. ESR spectra of Fe(III) complexes of DPE 29:
(A) FePCl: (B) FePOH. 770K in CH2C12.

209

.mH mma mo Xmameoo

Ho UNSHAAHHHme mzp mo wmvoomm mzz ma pcmchamp muspmmmasme .H:< mummHm

7)) l?

 

 

)L)

 

 

 

 

 

 

 

 

 

 

 

 

 

07 n—..

(\J\

oO

 

 

JDW l

oONi

 

Oomni

 

210

.m& man no meageoc
HQNASH HhmcopvmaHHHvom on» mo asapoonm x22 xa ammcsoqoc mmspmmomeoa .Ndc omswwm

 

 

 

 

 

 

 

 

0 ON1 OVI Owl
LbrLbIP—beurPLbbLhL—bbbthbbrbLLbbL—P)PL~LL)L
mO
Othl

.....zue ....a .

 

 

211

.m# man no meQSOU
HoNAaHmziavaHHHvom map mo manomam mzz :H acmvanmc mmzpmmngoa .m:< whamHm

 

 

 

 

 

 

Uimn'

 

 

 

 

 

 

 

 

212

.HH Camaznmonoflpo
no Noamsco HQNBHAAHHHme ecu go sampomgm mzz :H mmmummmnsma soom .::< mmsmwm
mi 07: 0.1

o
rLFPIFrPFFF+PheLPFFPlFL

 

 

 

 

213

.u.
_

.Ammv «can» .mmomfimvmsauconmxosHisv

mo Kmagsoo_HoNeHmAHHvam may no ssmpomnm mzz xa mumpmmonsmp soom

nu Av... AVN..
_ _ i t . i i . i i . L.L . t ..L

I i. F bib D LL.D ’* DLLL (P P I

.n:< enemas

nunri
i _.t

L (-

*

L

h

 

 

 

 

 

214

 

 

 

 

 

acid
I A A A A. A I A A l l A A l A A l A
AL —I A A A A A LA I A A A l A A. A l A A
no I. ! I. "-

 

Figure A46. 60 MHz 1H NMR spectrum of m-(a-bromo)toluoy1

 

 

 

chloride.
I! p
i i
co2w r i
1 i
T s
'i
f. *
at
I
I; ‘
-1A.!Leiii.1A-- I - L-
4-4;-IJ-LAI----I-- -IA-i-I.--- -.-‘fi.
IO." Q" 00 $0 on u .... A c

Figure A47. 60 MHz 13 NMR spectrum of 3.5 (BrCH2)2-
benzoic acid.

215

 

 

A A '
_A_ l A A A A l A A A

A - ‘ A - -
l A A J A A A A I A_ l A A l L A A L 414 A A A I A
10 . . 7 C 5

Figure A48. 60 MHz 1H NMR syectrum of the monomethyl
ester of dipicolinic acid.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure A49. 60 MHz 1H NMR spectrum of methyl 2-(5-
carboxyl)acetylpyridine-6-carboxylate.

216

)(2

 

ABSORBANCE

 

300' '400 ' 500 ' 600 700

Figure A50. Electronic spectrum of the Fe(III)POH complex
of his aminodiacetic acid DPE 52 in water.

217

2 i m m o ... m 2:
.mm QMHOHSO ...—o i .m .pm 00 Z .
.mm unapmxocoe .o u 5.x .mv “my mo mmuomnm msz xa um: omN Hm< mmsmam

.N nu .N .v _w a .nu.

I I I I - I I I I — I I I I I I I — I I I I I I — I I I I I I - I I I I _ I I P
I I I I _ I I
I — - I I I P (P P I I I — I+ I I I I

 

 

 

 

 

 

 

 

... m a ...

 

 

 

218

II l. I l- . I I F

.mm cmcoage eepmamxam mo asupoeem mg: :H ex: omm .~m< omsmmm

w... o N .v w m

0.

tfiTbLL‘b—Ir*Il—tb‘l—LLLl’b b PLbe—bLL’L _L‘thbL‘Li—IIL bLLllIblIl—hblfi p—LILL

 

 

4W

. J 4% J

 

 

 

 

 

fill.

 

219

.mm camoano cmpmahxam mcmahcpme mo asepomam mzz ma um: onN .nm< mmsmfim

.lplPWMLl.ell.lw...._.rl.w.._._.l..¢ a 4._l._.ll

(_bbblP—FrfibpbPhrhbbbb

his]?

 

 

 

 

 

 

 

 

 

 

~10

220

.mN unopmxwo o .N mo xmaneoo cams one mo eshuomnm msz :a ax: omN .:m< mummHm
i o e o. m o.
rlllmlll.Pilll_.....rl..Wllllerlllhllllbl.llpllllellllp.»ll_-l_.Fl.

 

 

J

 

 

 

 

 

D

 

 

 

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221

 

 

 

 

 

 

 

 

 

 

 

 

i) if

 

 

 

mwmcee >um.

11‘ ‘ )1 i q 6 11111lq4i 4 4 i1).— +f<Tfifi+++m+ 44'1l-i4 4 1+

m . b

mmo 3am H: 23w meanness ow wwwwwmdmo dmoammwoovponw: mm.

q.+
nu

222

.mm :mtoaeo eaoumomeH omxcma memes mo esteoeam mzz :H ex: omm .om< ecsmmm

 

 

 

 

 

 

 

 

 

o N ¢ . 0 o.
->r>)—»»>r~ iii pill._.l.. mlprirl..lb.
\II
on
\J I
Z(2/>.\z

OI

223

.mm mamoano cmpmumCmm Mappfiz no sampommm mzz ma ax: onm

i. u.

«be

c-ib

"-6

.mma mustm

O—

 

 

«l-
_—

 

 

 

 

 

 

 

 

 

 

623.10on

 

    

 

224

 

it u .Aaav mommomzo u m Anv
.Ammv pmuoo mo u m Adv imamungo eeuaasxae no amputee ms: ma ax: onw

.mna ecswmm

225

 

m o.

I—hLbD—‘FLLbLbLL—tLb_Ilfl

 

‘ I7

 

 

 

 

 

 

I z
3 ....-

 

mil).
4

 

 

 

 

 

226

o

.mw cmueano «HoumcmeH cexcma cepme mo estpoeem mzz ma ex: onm

_I N _¢
.LE.

.mma et=Mmm

.@ m. nu.

bLbLbbbb LhprblPLbIlbLl-bl—rLLPLthbb—FLLL~thbl—LthbLth—bbDbl—LLfiL

 

‘

 

 

 

 

fillllli

 

 

 

227

 

it .mm cmuoanoemeoeoanomm .e: u .m .:o u m Anv
.mm oeoeexme m.~ .o a bum .mv Adv mo amputee mzz mm a:: omm

.004 etswmm

228

N... 2a.... 0 N v w m 0.

Lb: Ibhlb (IbLlP LrLb LbLIb LhLLP LLLVIb bbLb bble LFFL LL‘L LLLL bleL

l? J .

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

)1 J33]? m
.c
c

IWO‘I II‘xIlI‘IflFIQ".ll-..C 7,,U‘Oliail...’ D56: II o'— I'lc I V. faLJV

 

i(\
Aw

m MNiV 3.53800 rad Hw Ali 0 m“ i o I A . VA 0 7— V n «B V ..u c dirk drierwabmi ”py).—z vb H .N. '5)— »lvml. it i GAVIN ariflfimm .A, ..ilfl

229

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A_J- L'JLL (UL
3* K.)_ Le '

["V'l"VTIV'f'lftfv[rffvlfVTrrr'ffrrvfivv'var'fvfi

8 6 4- 2 (J

 

Figure A61. 250 MHz 1H NMR spectra of alkylated iso-
bacteriochlorins: (A) R = OH (2g): (B)
R = H (29).

230

 

it .AHOHV emeoNxooo u m Amy
.Aooav z u m A<V .mcwmoanoowmmvomnomm cmpmazxam mo mmuomgm «:2 ma ax: omN

.moe ecstm

231

u ... .
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Figure A64. 60 MHz 1H NMR spectrum of 3-(N-imidazoly1)
propylamine. neat.

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Figure A65. 60 MHz 1H NMR spectrum of N-acetyl 3-(N-
imidazolyl)propylamine. D20.

234

 

 

 

 

 

 

 

 

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Figure A66. 60 MHz 1H NMR spectrum of N-isopropyl 3-(N-
imidazolyl)propylamine. D20.

 

 

 

 

Figure A67. 60 Mfiz 1H NMR spectrum of N-acetyl N-isopropyl
3—(N-imidazolyl)propyl amine.

235

 

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Figure A68.. 60 MHz 1H NMR spectrum of methyl 3-(N-
imidazolyl)proprionate, neat.

 

 

 

 

 

 

      

 

 

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Figure A69. 60 MHz 1H NMR spectrum of ethyl 2-(N-
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236

   
   
 

 

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Figure A70. 60 MHz 1H NMR spectrum of h- (N- imidazolyl)
butyronitrile. neat.

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Figure A71- 60 MHZ 1H NMR spectrum of h-(N-imidazolyl)
butyric acid, D20.

237

 

 

 

 

 

 

 

 

 

 

 

 

C
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D
Volts vs SCE
I F I 1 T T I 1
o -005 -100 -105 -200

1.5 1.0 0.5

Figure A72. Cyclic voltammograms of (A) tetraphenylporphyrin;
(B) tetraphenylchlorin; (C) Zinc-TPC; (D) tetra-
phenylbacteriochlorin. Spectra measured in CHZClZ
with (Bu)4NC104 as supporting electrolyte.

List of References

 

238

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