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Synthesis of Some Protic PicketFence Porphyrinatocobalt(II)Complexes and Their Reactions withDioxygen as Hydrogen-Bond Modelsin Oxy HemoproteinsHiroyasu Imai a , Akiko Nakatsubo a , Shigeo Nakagawa a ,Yoshio Uemori a & Eishin Kyuno aa Department of Pharmaceutical Science , School ofPharmacy, Hokuriku University , 3, Ho Kanagawa-Machi,Kanazawa, 920-11, JapanPublished online: 06 Dec 2006.

To cite this article: Hiroyasu Imai , Akiko Nakatsubo , Shigeo Nakagawa , Yoshio Uemori &Eishin Kyuno (1985) Synthesis of Some Protic Picket Fence Porphyrinatocobalt(II) Complexesand Their Reactions with Dioxygen as Hydrogen-Bond Models in Oxy Hemoproteins,Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry, 15:3, 265-286, DOI:10.1080/00945718508059387

To link to this article: http://dx.doi.org/10.1080/00945718508059387

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SYNTH. REACT. INORG. MET.-ORG. CHEM., 15(3), 265-286 (1985)

SYNTHESIS OF SOME PROTIC PICKET FENCE PORPHYRINATO- COBALT(I1) COMPLEXES AND THEIR REACTIONS WITH DIOXYGEN

AS HYDROGEN-BOND MODELS IN OXY HEMOPROTEINS

Hiroyasu Imai, Akiko Nakatsubo, Shigeo Nakagawa, Yoshio Uemori, and Eishin Kyuno*

Department of Pharmaceutical Science, School of Pharmacy, Hokuriku University,

3, Ho Kanagawa-Machi, Kanazawa 920-11, Japan

ABSTRACT

Some specific picket fence porphyrinatocobalt(I1) complexes were newly synthesized and characterized. The complexes contain one protic substituent capable of forming intramolecular hydrogen bond with the dioxygen molecule coordinated to the central metal ion. Their reactions with dioxygen molecule were measured spectro- metrically in solution containing an axial base, and the thermodynamic functions were determined. The results indicate that the protic groups promote the irreversible oxidation of Co(I1) to Co(II1). This effect may be ascribed to decreased electron density at the central Co(I1) ion, which is resulted from shifted electron density toward the hydrogen atom of the protic group through the coordinated 0 2 molecule by hydrogen-

265

Copyright @ 1985 by Marcel Dekker, Inc. 0094-5714/85/15034265$3.50/0

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266 IMAI ET AL.

bond formation o r t h e l i k e . I t is a l s o found t h a t t h e

complexes prepared have lower 0 2 a f f i n i t y t h a n t h e

corresponding complexes w i t h no p r o t i c s u b s t i t u e n t and

t h a t t h e decreased b ind ing energy - A H a of t h e dioxygen molecule t o t h e complexes b r i n g s abou t t h e inc reased f r e e energy A G O .

INTRODUCTION

The r e l a t i o n s h i p s between s t r u c t u r e s and func- t i o n s of hemoglobin and myoglobin have been s t u d i e d

widely i n both n a t u r a l and model systems '-17. I n model systems, some t y p e s of c a v i t i e s w e r e i n t roduced t o a po rphyr in o r macrocycl ic molecule i n o r d e r t o m i m i c t h e e f f e c t i v e and r e v e r s i b l e oxygenat ion o f n a t u r a l systems. A s one of t h e s e approaches, Collman e t a l . developed t h e p i c k e t f ence t y p e po rphyr ina to complexes

They w e r e t h e most e f f e c t i v e i n model systems,

a l though t h e n a t u r e of t h e c a v i t y governing t h e s i x t h l i g a n d a f f i n i t y of t h e c e n t r a l metal i o n i s s t i l l ques- t i o n a b l e i n de t a i1415 . On t h e o t h e r hand, i n n a t u r a l systems, it w a s found t h a t any of t h e amino a c i d r e s i d u e s forming c a v i t y r e g u l a t e s t h e O2 a f f i n i t y

and/or t h e r e v e r s i b i l i t y of oxygenation r e a c t i o n by t h e s t u d i e s on mutant hemoglobins and myoglobins6-8. The imidazole group of d i s t a l h i s t i d i n e (E7) i n t h e c a v i t y l i e s most c l o s e l y i n space t o t h e c e n t r a l m e t a l so t h a t

s ter ic and e l e c t r o s t a t i c i n t e r a c t i o n s may appear between t h e group and t h e coord ina ted s m a l l molecule, i . e . , 02, CO, o r etc. , as a s i x t h l i g a n d . The s ter ic i n t e r a c t i o n s may p lay an impor t an t r o l e , f o r example,

t o r e g u l a t e t h e CO a f f i n i t y o f heme. I n t h i s r e g a r d ,

some works have been done 4r9-11 by u s i n g model systems. A s a t y p i c a l example of e l e c t r o s t a t i c i n t e r a c t i o n s , "hydrogen-bond formation" between t h e imidazole group and t h e coord ina ted dioxygen molecule may be exp la ined ,

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PICKET FENCE COMPLEXES

H i s E7

267

0 io

H i s F8

The presence of the hydrogen bond in oxy hemoproteins has been demonstrated by neutron diffraction , X-ray dif fraction13, ESR , and resonance Raman14 investiga- tions. It has been thought that the hydrogen bond stabilizes the bond of dioxygen molecule to hemopro- teins. However, the effects of the hydrogen bond on 0 2

binding energy to the whole molecule and on 0 2 reversi- bility of oxygenation are not known in detail. Although only one attempt to investigate the former problem has been done in model systems by Momenteau g - a d 5 , its results did not answer satisfactorily to this problem.

In order to clarify the effects of intramolecular hydrogen bond on oxygenation of hemoproteins, some specific model complexes were newly designed and synthesized. The complexes were picket-fence type porphyrinatocobalt(II), where one of the substituents forming the fence was replaced by certain protic substituents capable of forming hydrogen bond with the coordinated dioxygen molecule (figure 1). In solution containing 1-methylimidazole as an axial ligand, the

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268 IMAI ET AL;

Y = 2H Y = Co(I1)

X = -CH2-OH H2tNHP (la) [Co(tNHP)] (5) -CH2-CO-NH2 H2tNC3AP (a) [Co(tNC3AP)l (E) -CH2-CH2-CO-NH2 H2tNC4AP (g) [CO( tNC4AP)] (a)

H2tNHPP (9) [Co(tNHPP)] (5) G FIG. 1. The s t r u c t u r e o f p i c k e t fence porphyr in d e r i v a t i v e s .

X i s a p r o t i c subs t i t uen t .

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PICKET FENCE COMPLEXES 269

reactions of these complexes with dioxygen molecule were measured spectrometrically. The effects of hydrogen bond or the like on 02 reversibility and on 02 binding were examined, on the basis of life times of the complexes in solution under 02 atmosphere and of the caluctaled thermodynamic values on oxygenation.

RESULTS AND DISCUSSION

Synthesis. The picket fence of all of the complexes prepared consists of three aprotic and one protic substituents (in addition to amido groups). The protic substituent has a suitable molecular dimension for forming hydrogen bond with the dioxygen molecule coordinated to the central metal ion. The other three aprotic substituents make the complexes easily soluble in aprotic organic solvents so that the equilibrium measurements in solution can be carried out, although the protic group has a trend to decrease the solubility in the solvents. Fortunately, since these types of the complexes containing the same kind of aprotic substitu- ents have been already well characterized2' 5, the ef- fects of one protic group in the fence of the complexes on dioxygen binding could be examined precisely by comparison with the corresponding complexes containing the same kind of aprotic substituents as a picket fence.

In this work, three neopentyl groups (-CH2- C(CH3)3) were introduced as aprotic substituents, although pival groups (-C(CH3)3) have been convention- ally used as a picket fence. The reasons for the use of the former are as follows. First, the complex containing the former has higher 0 2 affinity than that of the latter . Secondly, the complex with the former is more soluble in organic solvents than that

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270 IMAI ET AL.

with the latter. Actually, the purification and equi- librium measurements of some of the complexes prepared were carried out more easily than the corresponding complexes containing pival groups.

In the process introducing the three neopentyl groups into -0-tetrakis (a4-o-aminophenyl) porphyrin (a4-H2TamPP), some by-products were formed in statisti- cal abundance. Each of the by-products contains four, two, or one neopentyl group, and these by-products were not easily separated by conventional column chromato- g r a p h ~ ~ , because of their similar Rf values on TLC. In the preparative process of compound la, 2a, and 3a, further derivation of the mixture containing the by- products makes the Rf values of their derivatives easily distinguishable. Accordingly, removal of the by-products was accomplished in the last stage in schemes 1 and 2. In the case of compound 4a, this procedure was not applicable because of the similar Rf value of 4a to those of the corresponding derivatives of the by-products. Consequently, another procedure was devised to prepare the porphyrin containing three neopentylcarbonylamino groups and one amino group (scheme 3). This synthetic method gave the desired porphyrin in satisfactory yield by conventional column chromatography. Additionally, the by-products obtained in this scheme were easily converted to the starting material, a4-H2TamPP, by hydrolysis. Compound - 6 was also able to give compounds 5, - 2a, and - 3a in good yields by treating with the corresponding reagents.

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-

1~ NMR spectra. Figure 2 shows 1H NMR spectrum of compound 3a as an example. Any amino proton signal is unfortunately not observed here, although the presence of the amino group is evident by TLC and elemental analysis. The resonance signals at -2.70 (2H), 0.48

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P I C K E T FENCE COMPLEXES 2 7 1

a4-H2TamPP

SCHEME 1.

n = l : HztNC3AP (a) n=2: HztNC4AP (a)

SCHEME 2.

(separa t ion)

SCHEME 3.

X X

SCHEME 4.

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272 IMAI ET AL.

-5 PW L I I

10 5

FIG. 2 . 1 H NMR spectrum o f HZtNC@P. In C D C 1 3 .

(27H), 1.28 (6H), and 1.7-1.9 ppm (4H) are assigned to pyrrole NH, methyl, methylene (aprotic substituents) , and methylene protons (protic one), respectively. The signals of the other protons are observed at 6.8-8.8 ppm (29H). In the case of compound 5 (figure 31, the phenolic hydroxy proton signal is observed at 11.45 ppm (1H). The methyl signals of - 4a are separated with a ratio of 2 : 1 at 0.10 and 0.84 ppm. Similar phenome- non also can be seen for the methylene protons at 1.5- 1.7 ppm. These results can be understood in terms of ring current shifts of the phenyl group in the cavity, _ _ i.e., the plane of phenyl ring of the protic substitu- ent is perpendicular to the adjacent two aprotic groups (-CH2-C(CH3) 3 ) , and the other one group is nearly coplanar to the phenyl plane.

Reactions in Solution. The major reactions among porphyrinatocobalt(I1) (COP) , axial base (B) , and

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PICKET FENCE COMPLEXES 273

CH2 H co bc

1 1 1 ' 1 I I 1 I 1 I ' I

10 5 0 ( P P d

FIG. 3. 'H- NMR spectrum o f H2tNHPP. I n pyridine-dg. *: Impurity.

dioxygen molecule in solution are as follows;

CoPB Kg .

COP + B -

CoPB + 02 Co(II1)PB.X ( 3 )

where X is 02H- or others, and the reactions (1) and (2) are reversible and ( 3 ) is irreversible. These reactions were measured spectrometrically. I n this work, 1-methylimidazole (1-MeIm) was used as an axial base. The equilibrium constants KB for the reaction (1) were in a range of about lo4 to lo5 11101-1. On the basis of irreversible spectral changes (figure 4 ) , half lives of the complexes under O2 atmosphere were esti- mated. On the reaction (2) (figure 5), the equilibrium

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2 74 IMAI ET AL.

1 I I I I I

Wavel ength/nm 460 500 540 580

FIG. 4. Visible absorption spectra on oxidation of CCo(tNC3AP) (1-MeIm)]. At 25 "C in toluene under 142 atmosphere.

1 : 0 Torr 02 i t 2: 99 -. _ _ 3: 197 4: 297 5: 393 6: 495

460

, 7: 598 L 8: 702

500 540 580

Wavel ength/nm

FIG. 5. Visible absorption spectra on oxygenation o f [Co(tNHP) (1-MeIm)] at 25 "C in toluene.

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PICKET FENCE COMPLEXES 2 75

data P1l2 (half-saturation O2 pressure, and that is equal to KO,-’) were calculated by the published procedure2’ with corrections of the above irreversible spectral changes. As reference complexes, 7 and - 8 were used in these experiments.

-

[Co(a4-TneoPP)] ( L ) [ Co ( a3-TneoPP) 1 (8)

The protic groups of the complexes prepared were not coordinated to cobalt atom, so that the complexes were four-coordinated in solution in ‘the absence of axial base for the following reasons. (1) Addition of axial base to the COP solution caused a marked visible spectral changes attributed to formation of CoPB as a five-coordinated complex. ( 2 ) In 1~ NMR measurement,

the methyl signals of the complexes were observed at appreciablly high field (see experimental section) by paramagnetic shift attributed to the cobalt(I1) ion. This is due to an unpaired electron on dxy orbital, and it is a l so characteristic of square planar four-coordi- nated complexes. In five-coordinated complexes, the unpaired electron is on d,2 orbital l6 so that the methyl signal is not so much shifted. For example, the methyl signal of complex 1 was observed at -3.0 ppm (CDC13) (four-coordinated complex), while addition of

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276 IMAI ET AL.

TABLE I

Half-life of Porphyrinato Complexes under 02 Atmosphere.

compl ex sol vent ha1 f -1 i fel h

[Co(tNHP)] & to1 uene 2

[Co(tNC4AP)] 2 to1 uene 4

[Co(a3-TneoPP)] 8 to1 uene QJ20

[CO( tNC3AP)I to1 uene 1.5

[Co(tNHPP)] to1 uene a

to1 uene-MeOH /9:11 1.4 .- ,

At 25 OC. Axial base = 1-methylimidazole. a: Rapidly oxidized.

pyridine-d5 as an axial base to the complex solution gave rise to shift the signal to 0.0 ppm (five-coordi- nated complex).

lrreversible oxidation. The complexes containing a protic substituent on the picket fence are oxidized more easily than the complexes with no protic one.other than amido groups (table 1). It may be suggested that the protic group on the fence of the complexes prepared promotes the oxidation of Co(I1) to Co(II1). In other words, the formation of hydrogen bond or the like between the protic group on the fence and the coordi- nated dioxygen molecule would accelerate the irreversi- ble oxidation of the central metal ion from M ( I 1 ) to M ( I I 1 ) . This result agrees with the Peruzt's sugges- tion17 that permanently protonated protic group should promote rather than inhibit oxidation of the metal. It is also found in the table that addition of a small amount of methanol to the solution accelerates remark- ably the oxidation of the central metal ion. Presum-

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PICKET FENCE COMPLEXES 277

ably, the hydroxy group of methanol in solution might

act similarly to the protic group in complexes - s. Complex - 4b is the most readily oxidized of the

complexes prepared. It is also interesting that the mutant hemoglobins Boston and Saskatoon, in which only the distal histidine ( E 7 ) in either a- or 8-chain is replaced by tyrosine, respectively, are readily oxidized in only the replaced chain6. Since both compounds 4b and these mutant hemoglobins have the same phenolic hydroxy group near the central metal ion, this phenomenon on complex 4b may be quite reasonable.

-

p r o t i c group -X

\@- . . A$*O 0 /

I A+ p o r p h y r i n p lane I C O -

I /N\

a x i a l base

It may be concluded that strong hydrogen-bond formation between a protic group and coordinated dioxy- gen molecule would cause the irreversible oxidation of the central metal ion. It seems reasonable to assume that the decreased electron density on the coordinated dioxygen molecule reduces substantially the charge on the central metal ion, followed by oxidation from M(I1) to M ( I I I ) , when a protic group forms strong hydrogen bond with the coordinated dioxygen molecule.

Reversible oxygenation. Table 2 shows P112 values for the reaction (2). It has been reported5 that intimately packed geometry of cavity increases the O2

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278 IMAI ET AL.

TABLE I1 Equilibrium Data on Oxygenation o f Porphyrinato Complexes.

complex P112lTorr

[Co(tNHP)] 1,300

[CO( tNC3AP)I b [Co(tNC4AP)]

[Co(cc4-TneoPP)] z

1,600

800

120

[Co(cc3-TneoPP)] 6 800

At 25°C in toluene. Axial base = 1-methylimidazole.

a f f i n i t y ( d e c r e a s e s t h e P1i2 v a l u e s ) of t h e c e n t r a l me ta l i on . I f t h e s p e c i a l i n t e r a c t i o n s between t h e

p e r i p h e r a l s u b s t i t u e n t s of t h e p i c k e t f ence and t h e

coord ina ted dioxygen molecule i n complexes - 3b w e r e a b s e n t , t h e P1l2 v a l u e s of t h e complexes should be i n t h e range between t h o s e of complexes - 7 and S by steri- ca l c o r r e l a t i o n of t h e c a v i t y . I n p r a c t i c e , t h e l a r g e r

v a l u e s of P1/2 of l b - 3b than t h o s e of I. and - 8 may i n d i c a t e t h e presence o f t h e s p e c i a l i n t e r a c t i o n s .

Th i s r e s u l t s u g g e s t s t h a t t h e p r o t i c group of l b - 3b

i n c r e a s e s t h e P I / ~ v a l u e and t h a t hydrogen-bond formation o r t h e l i k e between t h e p r o t i c group and t h e

coord ina ted dioxygen molecule lowers t h e O2 a f f i n i t y ,

as opposed t o t h e p r e d i c t i o n t h a t t h e hydrogen bond

would s t a b i l i z e t h e 0 2 bonding t o t h e whole complex molecule.

I n o r d e r t o e l u c i d a t e t h e e n e r g e t i c c o n t r i b u t i o n t o t h e lower 0 2 a f f i n i t i e s of t h e complexes prepared, thermodynamic v a l u e s w e r e e s t ima ted f o r complex 3 a s an example. I t c a n be seen from t a b l e 3 t h a t t h e

dec reased b ind ing energy - A H o of t h e dioxygen molecule t o complex 3b b r i n g s abou t t h e inc reased f r e e energy

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PICKET FENCE COMPLEXES 279

TABLE I11

Thermodynamic Values on Oxygenation of Porphyrinatocobal t( 11) Complexes.

AH O ASob AGO^ compl exa kJ mol-l kJ K-1 mol-1 kJ mol-1

[Co(tNC4AP)] -38.5 f 1.7 -130 f 13 0.13

CCo(a4-TneoPP)l rc -55.2 -170 -4.58

CoMbd -55.6 -1 65 -6.42

[Co( PPIXDME)Ie -40.6 -1 58 6.62

Ax ia l base = 1-rnethylirnidazole, in toluene, except CoMb.

b: Standard s ta te 1 atrn 02; a t 25 "C. so lu t ion, pH 7, 0.1 mol d V 3 phosphate ion; Ref. 19.

a: Ref. 18. c: Ref. 5. d: I n aqueous

e: Ref. 20.

AGO. As one of major reasons for the apparently low binding energy of 0 2 to the complex, the following reason may De considered. The protic group forms

hydrogen bond with excess free 1-methylimidazole or with the adjacent amido group in the deoxy five-coordi- nated complex, while the protic group in the oxy six- coordinated complex is bound with the coordinated dioxygen molecule. In the complex, the extra binding energy of the dioxygen molecule by the hydrogen-bond formation would be cancelled out by the cleavage of the former . In the deoxy five-coordinated state of natural systems, the protic group (distal histidine) is rigidly but freely (with no hydrogen bond) forming a part of cavity, while this is not the case with this model system.

There might not be an appreciable difference in the oxy six-coordinated state between natural and the present model systems. In both systems, electrostatic interactions in the vicinity of an active site would be present. Further investigations (X-ray, ESR, and etc) on this model system will clarify the problem.

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280 lMAI ET AL.

EXPERIMENTAL

Measurements. The UV and visible absorption spectra were recorded on a Hitachi 340 recording spectrophoto- meter. The equilibrium data were estimated by the published procedure2 5. The thermodynamic values were determined by the temperature dependence of P1/2 in a range of OQC to 25OC. The lH NMR spectra were obtained from a JEOL JMN-MH-100 spectrometer.

Synthesis. meso-Tetrakis (a4-o-aminophenyl) porphyrin ( a4-H2TamPP) was prepared according to the literature' 21. meso-Tetrakis [a4-o- (neopentylcarbonylamino) phenyl] porphyrinatocobalt (11) ( [Co (a4-TneoPP) 3 , 1) and the corresponding a3-atropisomer [Co(a3-TneoPP)] (8) were obtained by the published method5.

Acetoxymethylcarbonyl chloride. Glycolic acid (10 g) was dissolved in tetrahydrofuran (350 ml) and triethyl- amine ( 3 0 ml). Acetyl chloride (25 g ) was added dropwise slowly to the above solution in an ice bath. After addition of benzene (150 ml), the mixture was filtered. The filtrate was concentrated on an evapora- tor. Benzene (5 ml) , dimethylformamide (1 ml) , and thionyl chloride ( 3 5 ml) were added to the oily resi- due. The mixture was refluxed for 20 min. Acetoxy- methylcarbonyl chloride was obtained as colorless liquid by distillation (94OC, 2 0 mmHg), yield 11 g ( 6 7

% ) . IH NMR (CDC13): 2.18 ( 3 H ) , 4.96 (2H).

- meso-Tris[a~-o-(neopentylcarbonylamino)phenyl]mono[a- o-(hydroxymethylcarbony1amino)phenylporphyrin (H2tNHP, la). a4-H2TamPP (2 g ) was dissolved in dry CH2C12 ( 8 0 0

ml) and pyridine (2 ml). Neopentylcarbonyl chloride (1.25 ml) and pyridine (2 ml) were dissolved in CH2C12 ( 8 0 ml). The solution was added dropwise slowly to the above porphyrin solution in an ice bath. After 2

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PICKET FENCE COMPLEXES 281

h, acetoxymethylcarbonyl chloride (2 ml) was added to the solution, and the mixture was stirred for 2 h. The solution was evaporated, then dissolved in tetrahydro- furan (200 ml). Aqueous NaOH (4g/30ml) was added to the porphyrin solution, and the mixture was stirred for 2 h at room temperature. After neutralizing with HC1, the mixture was concentrated, yielding purple solid. The solid was filtered off and washed well with water, then dried in vacuo. The product was purified by column chromatography (silica-gel, 3 X 40 cm, CH2C12- ether = 1O:l; second band), yield 1.0 q (30 9 0 ) . IH NMR (CDC13) -2.67 (2H), 0.43 and 0.44 (27H), 1-20 - 1.34 (6H), 3.64 (2H), 7.06 - 9.02 (28H). Anal. Calcd for C64H66N805: c, 74.83; H, 6.48; N, 1 0 . 9 1 % . Found: C,

74.73; H, 6.40; N, 10.93 % .

- meso-Tris [a3-0- (neopentylcarbonylamino) phenyl] mono [a- o-(carbamoylmethylcarbonylamino)phenyl]porphyrin (H2- tNC3AP, 2a). a4-H2TamPP (2 g) was treated with neopentylcarbonyl chloride in a similar manner to that of la. After 2 h, malonyl dichloride (2 ml) was added dropwise to the porphyrin solution in an ice bath. The solution was stirred for 20 min, then gaseous ammonia was bubbled for 5 min to the solution. After filtra- tion, the filtrate was evaporated to dryness. The solid was purified by a silica-gel column (3 X 40 cm, CH2C12-ether = 5:l; second band), yield 0.9 g ( 2 9 % ) .

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IH NMR (CDCI-3) -2.67 (2H), 0.50 (27H), 1.33 (6H), 2.60 (2H)r 7.00-8.92 (29H). Anal. Calcd for C65H67Ng05: C, 74.05; H, 6.41; N, 11.96%. Found: C, 73.33; H, 6.47; N, 11.45%.

meso-Tr~s[~~-o-(neopentylcarbonylamino)phenyl]mono[~- - o-~2-carbamoylethylcarbonylamino)phenyl]porphyrin (H2- tNC4AP, - 3a). This compound was obtained by an analogous method to that of 2a, by use of succinyl -

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282 IMAI ET AL.

dichloride instead of malonyl dichloride. lH NMR (CDC13) -2.70 (2H), 0.45 and 0.48 (27H), 1.28 (6H), 1.7-1.9 (4H) , 6.85-8.77 (29H). Anal. Calcd for C66H6gNg05: c, 74.20; H, 6.51; N, 1 1 . 8 0 % - Found: C, 73.57; H, 6.21; N, 11.44%.

meso-Tris(~~-o-aminophenyl)mono[~-o-(triphenylmethyl- - amino) phenyl J porphyrin (2) . This compound was obtained by modifying the procedure described in the literature '. a4-H2TamPP (4 9) was dissolved in dry CH2C12 (1000 ml) and triethylamine (1 ml). Trityl bromide (2 g) was dissolved in CH2C12 (300 ml) and added dropwise slowly to the porphyrin solution with stirring in an ice bath. The mixture was evaporated to dryness. The solid was

purified by a silica-gel column (5 X 15 cm, benzene- ether = 30:1), yield 3.3 g (61 % ) .

m=-Tris [a3-0- (neopentylcarbonylamino) phenyl] mono (a- Compound 5 (3 g ) was

dissolved in CH2C12 (400 ml) and triethylamine (2 ml). Neopentylcarbonyl chloride (2.2 ml) was added dropwise to the solution in an ice bath. The mixture was stirred for 1 h, then aqueous ammonia (10 ml) was added, removing the unreacted acid chloride. After 10 min, 6 N HC1 (400 ml) and acetic acid (100 ml) were added to the solution. The mixture was stirred for 3 h at room temperature. The resulting mixture was neutra- lized slowly with aqueous ammonia in an ice bath. The organic layer was separated and the aqueous layer was extracted with CH2C12 (100 ml). The combined organic layer was washed twice with water. The organic layer was dried over anhydrous Na2S04. After filtration, the solution was loaded onto a silica-gel column (CH2C12, 3 X 40 cm). The column was eluted with CH2C12-ether (20 : 11, yield 2.9 g (91 8 ) . lH NMR (CDC13) -2.73 (2H), 0.41 and 0.44 (27H), 1.24 (6H), 3.60 (2H) , 6.80-9.01 (2713).

o-aminophenyl) porphyrin (6) . -

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PICKET FENCE COMPLEXES 283

mS-Tris [a3-0- (neopentylcarbonylamino) phenyl] mono [ a - o-(2-hydroxyphenylcarbonylamino)phenyl]porphyrin (H2- tNHPP, 4a). Compound - 6 (1 g ) was dissolved in CH2C12 (500 ml) and triethylamine (0.4 ml) in an ice bath. 2-Acetoxybenzoyl chloride (1 g) was added to the solution with stirring. After 10 h, the solution was washed with dilute aqueous ammonia, then twice with water. The organic layer was dried over anhydrous Na2S04. The solution was evaporated to dryness. The solid was dissolved in acetone ( 2 0 0 ml). Aqueous NaOH (3 g/ 20 ml) was added to the solution, and the mixture was stirred for 30 min at room temperature. The mixture was neutralized with dilute HC1 and evaporated, yielding purple solid. The solid was filtered off and washed well with water. After drying, the product was purified by column chromatography (silica gel 3 X 30 cm, CHzClz-ether = 20 : 1) , yield 1.0 g (89 % ) . lH NMR (pyridine-d5) -2.60 (2H) , 0.10 (18H), 0.84 (9H), 1.57 (4H), 1.74 (2H) , 6.59-9.93 (28H) , 11.45 (1H). Anal.

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Calcd for CsgH68N805: c, 76.08; H, 6.29; N, 10.29 %.

Found: C, 75.90; H I 6.18; N, 10.10 % .

meso-Tr~s[a3-o-(neopentylcarbonylamino)phenyl]mono[~- o-~hydroxymethylcarbonylam~no)phenyl]porphyrinato- cobalt(I1) ([Co(tNHP) I , lb). Compound & (0.4 9) was treated with anhydrous CoC12 (0.4 g) in tetrahydrofuran (50 ml) and 2,6-dimethylpyridine (0.14 ml) at 45°C for 20 min under N2 atmosphere. Purification was carried out by a silica-gel column (3 X 30 cm, CHzClz-ether =

10 :1 ) , yield 0.2 g (53 % ) . 1 H NMR (CDC13) -1.75, -3.05 (methyl protons). VIS (toluene) 413, 528, 562 (sh) nm.

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Anal. Calcd for C64H64N805CO: c, 70.90; H I 5.95; N, 10.34 % . Found: C, 70.06; H, 6.05; N, 9.76 %.

F - T r i s [a3-,- (neopentylcarbonylamino) phenyll mono [a- o-~carbamoylmethylcarbonylamino)phenyl]porphyrinato-

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284 IMAI ET AL.

cobalt(I1) ([Co(tNC3AP)] , - 2b). This complex was obtained by the reaction of - 2a with CoCl2 in a similar

(methyl protons). VIS (toluene) 413, 527, 560 (sh) nm. manner to that of lb. 1 H NMR (CDC13) -1.9, -1.5 -

Anal. Calcd for C65H65Ng05CO: C, 70.26; HI 5.90; N, 11.34 % . Found: C, 69.82; HI 5.96; N, 10.84 % .

meso-Tris [a3-0- (neopentylcarbonylamino) phenyl] mono [ a - o-(2-carbamoylethylcarbonylamino)phenyl]porphyrinato- cobalt (11) ( [Co(tNC4AP) ] , 2) . This complex was obtained by the reaction of 2 with CoC12 in a similar manner to that of lb. I H NMR (CDC13) -1.8 (methyl protons). VIS (toluene) 414, 528, 560 (sh) nm. Anal.

__

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Calcd for C66H67NgOcjCO: c, 70.45; H, 6.00; N, 11.20 %.

Found C, 70.19: HI 6.05; N, 11.46 % .

m ~ - T r ~ s ~ a 3 - o - ( n e o p e n t y l c a r b o n y l a m ~ n o ) p h e n y l ] m o n o [ a -

o-~2-hydroxyphenylcarbonylamino)phenyl]porphyrinato- cobalt (11) ( [Co (tNHPP) I , - 4b) . This complex was obtained by the reaction of - 4a with C0C12 in a similar manner to that of lb. VIS (toluene) 413, 528, 560 (sh) nm. Anal. Calcd for C69H66NgO5Co: C, 72.30; HI 5.80; N, 9.78 % . Found: C, 72.31; H, 5.83; N, 9.71 %.

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ACKNOWLEDGMENT

This work was partially supported by a grant supplied by Japan Private School Promotion Foundation to which our thanks are due.

REFERENCES

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P I C K E T FENCE COMPLEXES 285

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J. P. Collman, T. R. Halbert, and K. S. Suslick, "Metal Ion Activation of Dioxygen" ed by T. G. Spiro, Wiley, New York, 1980, Chap. 1. J. P. Collman, J. I . Brauman, T. J. Collis, B. L. Iverson, G. Lang, 3. B. Pettman, J. L. Sessler, and M. A. Walters, J. Am. Chem. SOC., 105, 3038 (1983): J. P. Collman, J. I. Brauman, B. L. Iverson, J. L. Sessler, R. M. Morris, and Q. H. Gibson, H., - 105, 3052 (1983). H. Imai, K. Nakata, A . Nakatsubo, S. Nakagawa, Y. Uemori, and E. Kyuno, Synth. React. Inorg. Met- Org. Chem., - 13, 761 (1983). M. F. Perutz and H. Lehmann, Nature, 219, 902 (1968). M. Ikeda-Saito, T. Iizuka, H. Yamamoto, F. J. Kayne, and T. Yonetani, J. Biol. Chem., 252, 4882 (1977): M. Ikeda-Saito, H. Hori, T. Inubushi, and T. Yonetani, M., 256, 10267 (1981). P. W. Tucker, S. E. V. Phillips, M. F. Perutz, R. Houtchens, and W. S. Caughey, Proc. Natl. Acad. Sci. USA, - 75, 1076 (1978). D. H. Busch, L. L. Zimmer, J. J. Grzybowski, D. J. Olszanski, S. C. Jackels, R. C. Callahan, and G. G. Christoph, Proc. Natl. Acad. Sci. U S A , 78, 5919 (1981).

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Abbreviations used. CoMb, cobalt(I1)myoglobin; [Co(PPIXDME)], cobalt(I1) complex with dianion of protoporphyrin-IX dimethyl ester. B. M. Hoffman and D. H. Petering, Proc. Natl. Acad. Sci. USA, - 67, 637 ( 1 9 7 0 ) : C. A. Spilbulg, B. M. Hoffman, and D. H. Petering, J. Biol. Chem., 247, 4219 ( 1 9 7 2 ) .

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95, 6645 ( 1 9 7 2 ) .

J. Lindsey, J. Org. Chem., - 45, 5215 ( 1 9 8 0 ) : C. M. Elliott, Anal. Chem., - 52, 666 ( 1 9 8 0 ) .

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Received: 18 October, 1984

Accepted: 15 November, 1984

Referee I: I. Murase

Referee 11: S. Yamada

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