Synthesis and Structure of Biomimetic Porphyrins

Brian Morgan and David Dolphin Department of Chemistry, University of British Columbia, Vancouver, B.C., Canada V6T 1Y6

1. 2. 3. 3. A. 3.B. 3.C. 3. D. 4. 4. A. 4. B. 5. 5. A. 5.B. 5. C 6. 6.A. 6.B. 6.C. 6. D. 7. 8.

Introduction ................................................................................................................................ Porphyrins with Appended Peptides ........................................................................................... CheIatedHemes ......................................................................................................................... Porphyrins HavingCovalently Attached Imidazole or Pyridine Ligands ......................................... Porphyrins Having Covalently Attached Sulfur Ligands................................................................ Porphyrins with Covalently Attached Ouinonc Groups ................................................................. Porphvrins with Covalentlv Attached Interactive Groups .............................................................. "Picket-Fence" Porphyrins and Related Species ........................................................................ "Picket-Fence" Porphyrins............................................................................................................ "Tailed Picket-Fence" Porphyrins ................................................................................................ "Capped" Porphyrins and Related Species.................................................................................. "Capped" Porohvrins ..................................................................................................................... "Pocket" and "Tailed Pocket" Porphyrins ...................................................................................... "Bis-Pocket" Porphyrins ................................................................................................................ Strapped Porphyrins.................................................................................................................... Non-Functionalized Alkyl Straps.................................................................................................... Straps Containing Bulky Blocking Groups ..................................................................................... Straps Containing Interactive Groups............................................................................................ Doubly-StrappedPorphyrins .......................................................................................................... List of Abbreviations.................................................................................................................... References .................................................................................................................................

116 121 127 127 137 142 146 148 148 156 160 160 166 167 169 169 175 184 192 198 199

1. Introduction
Because have ing storage reduction idases in fore A sites. iron each their porphyrin an of iron heir ubiquitousness on as and
4

and

the

variety group,

of are

their

natural

functions, for and P450)5. IX), and the of oxygen b,

heme all c) ,
2

proteins containand oxygen (peroxsite the axial large active of the state, of Thereof

been

investigated porphyrin

multithe
3

and

interdisciplinary electron

levels.

These

proteins,

prosthetic

responsible utilization (cytochrome

transport

(hemoglobin (cytochrome and case ring

myoglobin)l and

transport

(cytochromes

oxidase) , an iron

hydrogen porphyrin essentially be

peroxide oxidation (usually planar

destruction The the nature nitrogens metal. of the of the a (spin

catalases) ', contains occupying of of be fully be

hydrocarbon

active

protoporphyrin coordination by the the of number

four

sites

diversity tenet may to

function

must

dictated is

ligands, the spin and oxidation state of the iron and the nature of he polypeptide chain. basic bioinorganic mimicked understand undertaken chemistry using the in that structure complexes heme protein of and to the function model metal biomolecules simpler which and inorganic the the

Obviously porphyrins state

mechanisms

function,

study

must and much

characteristics steric and has

oxidation

coordination of the

number) on (S 0).

electronic focussed which

effects on upon his the

porphyrin and other ligands are systematically varied. Historically, ism of proteins become (i) (ii) are research binding high spin (S to spin = metalloporphyrins and difficulty = The 2) iron(II) mechanheme is reversible five oxygen coordinate low myoglobin hemoglobin. species, in Oxygen binding

oxygenation behaviour

six-coordinate

reproducing

dominated by two problems: the irreversible oxidation of iron(II) porphyrins on exposure to oxygen, and the difficulty in obtaining well-defined five-coordinate iron porphyrins. Simple the iron(II) porphyrins iron(II) cannot reversibly is the bind oxygen, except by at low of temperature. a second rapidly in

At room temperature, and in the absence of a large excess of a sixth ligand, formation of six-coordinate down, dioxygen to a via species give ferryl immediately -peroxo to give followed bisiron(III) a u.-oxo attack complex. bisiron(III) five-coordinate breaks iron(II) complex This

presumably

intermediate

complex

which the iron has been irreversibly oxidized to the ferric form (Scheme I)8-11.

117

Therefore, the oxygen is irreversible porphyrins must being globin

major site,

role via by

for the to in

the

polypeptide the close

backbone of That

of two

heme heme by

proteins rings fact

is and that

to of the so,

sheath iron(II) body hemocomplex

binding oxidation

preventing ano her

approach is

consequent

[-peroxo reduce to ferric

complex.

irreversible the (the oxidized

oxidation iron(III) Even 3%. This of for

possible an of the in

mechanism the form acid to with

demonstrated functional

provide incapable exists is

enzyme oxygen body and occurs in is

methemoglobin to or the The the under

hemoglobin alternative protonated the the cytoFe11-O2

transport) the aqueous believed occur

iron(II) of conditions

form12. about where

extent

oxidation formation chromes species by

pathway

-peroxo

inhibited, Similar and

involve

proton production

assisted of chain also

formation stabilizes

superoxide13'.

oxidations cytochrome

superoxide,

P45014

oxidase3.

peptide

enclosing

the

porphyrin

in

hydrophobic

pocket

to

which

access

by

protons

is

inhibited.

In addition, recent neutron15 and X-ray diffractionl6 studies have indicated that stabili-

118

zation to

of

the

iron-oxygen bonding of

bond

in the

oxyhemoglobin terminal backbone changes the oxygen is upon

and

oxymyoglobin and the

may

in

part of

be the

due distal a are to is

hydrogen The

between the

atom

imidazole than at has simply the been iron the i.e., In by

histidine (His-E7). influence to to the an be avenue role protein tor more pervasive binding protein in of providing site barrier believed Similarly, provide the oxidation. Conformational of which oxygen on may the active

responsible along in

remarkable residues transfer

cooperativity occur sphere iron

exhibited the the is

hemoglobin17. postulated But it

arrangement

certain electron the

cytochromes.

protein's The second for Eq. 9,

maintaining problem in is =

coordination simple in over

porphyrin preference for the at of

which the

determines the functions of the various heme proteins. major studying example, favoured 10-30 in porphyrins metal N-donor ria the in six-coordination. K2 > K1 For solution at containing 25C)18. strongly benzene coordinating equilib25
0

ligands,

six-coordination (K2/K1

five-coordination,

aprotic solvent

binding the

constants The of one to

of
4

pyridine
-

to

Fe11(TPP) porphyrin high spin (S spin =

have is (S 0) for the

been in = Co", an 2)

estimated

at

K1 spin with is

1.5 (S a =

IO3 1) in on

M-1 state. a

and K2 ~1.9 x IO iron. Addition second field A nate which greater difficult.

M '. The size of K1 and K2 is obviously controlled by the spin state of iron the low In of intermediate five-coordinate species no of stabilization preparing of and mixed for models a to gives the complex which gain adds

four-coordinate ligand form

ligand

six-coordinate

crystal going

stabilization fur her iron the iron

energy19-20.

contrast, this by self is an

gained

from five- to six-coordinate since Co" is low spin in both cases, and K1 > K221). consequence A is difficulty mixed-ligand for thioether form system, a six-coordic in The porphyrins. typical of example is the preparation (His-18) its the with of are cytochrome (Met-80).

coordinated makes control have

imidazole coupled

ligating Strategies

power which

imidazole

tendency

six-coordinate Im-Fe-SR2, range in of

bis(imidazole)

complexes

assembly

ligand

coordination used to

essential oxidation

preparing

heme protein model porphyrins. Numerous approaches been control and coordination model oornhvrin svstems. (i) Excess Ligand: The presence of excess base (imidazole, pyridine) will minimize the

concentration of five-coordinate heme and reduce u-peroxo complex formation.

119

(ii) one

Low is

Temperatures22-'25. where to the reduced studying

Iron(II)-O2 competitive

porphyrin oxygen

complexes reactions as binding

are are K2/K1

stable

at as

low down.

temperAgain

atures

(~-60C),

irreversible

oxidation

slowed increases

temperature

decreases.

(iii) ible Ior

Kinetic oxygen has of to

Measurements: binding Im-Hm-CO, a short preferentially even the exploited

Fast under stability

spectroscopic conditions of with which at a a

me hods where mixture

may

be

used oxida ion and rate

to

observe will occur.

reversTrayA is In

irreversible of the oxygen carbon

imidazole-heme-CO dissociates fast but

complexes

towards carbon The >

(kBO2

oxidation26. monoxide, deoxy IO7 M-'s-1).

solution subjected then

equilibrated laser wi h pulse oxygen

monoxide.

heme

reacts

measurable

IO3 10s, the Im-Hm-O2 complex dissociates and returns to the Im-Hm-CO complex.

Since

kBCO in

is the

the

rate

of and

return
kB
2

before and k^
02

O2 may

is be

added,

kB

CO

may from a

be plot

accurately of l/krelurn

determined

experiment

calculated

vs O2 (pressure). (iv) Metal Substitution: which an Such Ru Replacement are approach In the more is of inert of iron to Co, with oxidation since cobalt28 and Co or possess may ruthenium29 different be leads to with

metalloporphyrins proper ies. Co and

coordination coopera-

applicable

apoproteins

recons ituted exhibits

porphyrins.

case

reconstituted

hemoglobin

tive oxygen binding although to a diminished extent. (v) diethyl The the This to approach a in solid a close be latter attempts support. matrix oxygen covalently approach attached and to oxygen of to In of prevent Wang's polystyrene two was to a prepared the in the was irreversible classic and observed. rigid a silica hemes oxidation a by heme a his with the

Immobilization: the ester matrix porphyrin was not or

anchoring

porphyrin only the

experiment30 but support. gel also

embedded

l-(2-phenylethyl)imidazole. provided and Alternatively, Basolo Reaction removed the iron(II) by support either which

prevented ligand may the the or

approach

hydrophobic colleagues contained Fe (TPP)(B)2 sixth axial However,

11

environment. have undertaken

Reversible

uptake attached and to heating give

3-imidazolylpropyl coordinated base to (pyridine

groups porphyrin

surface31. flowing helium five-coordinate obscured

piperidine) reversible

porphyrin. physisorp-

attempts

observe

binding

tion of oxygen by the silica support.

120

(vi) vented. rin

Steric of The in

encumbrance: two a approach polymer

By

sterically rings closely This of about been

blocking

one the

or u-oxo

both

faces is

of to

the

porphyrin, may the at and the the an sites of of be

close preto the ring steric porphyroom

approach ring

porphyrin most chain. doubts

and

therefore has oxygen

bridge system in of

formation pursued aqueous the or in

mimicking approach the

natural been and in binding

enfold solution

vigorously nature

attempt

prepare

compounds However,

capable

reversible

temperature. In are (i) (ii)

number

active both

reversibility of oxygenation have made this approach less fruitful. contrast, porphyrins by some have group(s) synthesized which to the one ring. faces obstructed covalently bonded The function

hindrance is two-fold: to direct base binding to the open face, ensuring five-coordination, and to allow O2 to bind on the hindered face, steric hindrance preventing u-oxo bridge formation. Five-coordination This ally may has model also be ensured used by in many e.g. these systems to by using a bulky wide axial bases of which cannot bind on the protected face. approach been groups produce variety architecturcrowned, different porphyrins, picket-fence, capped, cyclophane,

strapped, basket-handle, etc., which are discussed below. (vii) allows thioether, likelihood ligand On built-in sixand Chelated one of to Hemes: control etc., to long Covalent the covalent the as for (Eq. attachment of attachment without of the ligand For poor the of a to local addition pyridine, to the ligands large of porphyrin such excess a as of periphery thiolate, and the ligand a of external

extent metal

coordination. the

phenoxide, 15). other As

increases not

concentration

coordination

necessity occur,

(Eq. he 1:1

displacement strong 16), ligands As is

does e.g. long

second

allows formation of six-coordinate mixed ligand systems. hand, imidazole, as this chelation form produces provides mixtures base/porphyrin four-coordinate stoichiometry. dimerization, approach

prevented

five-coordinate

complexes.

In brance fixed energy gained. these

the and

following chelation hat have from

sections as models been the

we for

examine heme in ring. exist

those proteins. order Using of the

porphyrins We to the natural these also create

which review

employ a series with

steric of

encumat on be of will

biomime ic

porphyrins

synthesized porphyrin various reviews

complexes

quinones information can we properties

distances transfer Several models

models, the

important binding

between excellent and their

components which wi h

photosyn hetic ligand systems20,32-37.

apparatus Instead,

discuss

congruency

concentrate here on the strategy and synthetic details of model porphyrin preparations.

121

To

this

end,

the

compounds

have

been

grouped

toge her

more

in

terms

of

structure

than

of function. The reader is directed to reference 56 for a discussion on porphyrin dimers and strati bisporphyrins which are not reviewed here.

2. Porphyrins with Appended Peptides

Perhaps duce tide acids An (Scheme histidyl via the (e.g. early 2). the most to obvious a approach of the to the If synthesis active the of site the of acid the the of by heme protein models is to repropepamino heme various IX by la the IX and

local

environment

heme

covalently fragments

attaching contain sphere who of

various suitable the

fragments

suitable

porphyrin.

peptide

histidine, example After

methionine), of metal his

reproduction was the on to

coordination et

protein may be possible. approach to the into that Lautsch al.38', of coupled histidine-containing imidazole tripeptides was to propionic side-chains length ethyl of side the in mesoporphyrin coordination chain. of peptide

insertion were

porphyrin,

intramolecular chains

possible give

depending attached

Similarly,

histidine-containing sulfide

pep ides

mesoporphyrin Losse

linkages

2(b-d),

a situation similar

to that

cytochrome c.

Miiller39' coupled L-histidine methylester and protohemin 3 with dicyclohexylcar-

122

bodiimide histidine for various ethyl time

in bound di-

N,N-dimethylformamide. to of and to and The a to the the porphyrin imidazole tripeptide protohemin yield reaction in sulfonic methyl attached of the the of Hager41 3 to

However, acid, iron DMF the in

models the length centre. (e.g. in derivatives 6 with of a

indicated of the der Van

that, side Heijden of

with was et

a too

single short coupled and same and the had as 7a-e and prealso

propionic

chain

coordination

al.40',

fragments bispeptidyl mesohemin one or

P-Ala-His; the presence 4a-d

Gly-L-His; 3). At 5 side acids

L-Ala-L-His; the yielded chains such hemins histidine It was

Gly-L-His-Gly-OEt) Warme

triethylamine histidine

chlorocarbonate groups. sulfuric

(Scheme

prepared which ester to the

porphyrins both ei her model quite

containing the

appended complex acid amino both were to a low.

methionine mesohemin been histidine (Scheme methionine paration or

SO3/DMF propionic with or

anhydride,

converted 4). and

into A

anhydride. c

Subsequent

reaction mono7e, also and too

methionine covalently isolation that the and

yielded

disubstituted prepared.

potential

cytochrome products Momenteau the of 9a-c. from was quantities was

containing yields

porphyrin side et arms al.42),

was tedious were

Unfortunately allow of after

recognized intramolecular iron min a

peptide-containing characterized

short

unstrained deuterohe-

coordination. equimolar ester three 9c) was ester) of methyl

have

syn hesized Treatment and

five-coordinate followed by

porphyrin 8 with methyl

coordinating and more The

properties. triethylamine deuterohemin 16% yield

ethylchloroformate desired in

triethylamine, gave, and as a

L-histidine mixture methyl

dihydrochloride compounds separated 9b, and

purification, 6,7-

deuterohemin

6(7)-mono-(histidine deuterohemin mixture of isomers

ester

unreacted obtained

bis(histidine

(Scheme 5). The reduced iron(II) species was capable of binding oxygen reversibly at low

123

124

temperature dimerization

but of

oxidized the

irreversibly species

at

room occurred

temperature. at low

Furthermore,

extensive com-

5-coordinate

temperature

(-60C),

plicating oxygen binding studies.

similar To his of

dimerization stage the 8 three 5or all

was the

observed

for

the yielded

iron(III) model

species systems of which in attached was

at which

room are be in in a

temperature 6-coordinate, tedious. by to 20% the

in or

concentrated solutions. syntheses 6-coordinate la have mixtures prepared solvent after for and species, two with with separation covalently histamine 10 hydrochloric product 2 M could Castro heating of yield of

porphyrin

derivatives mesohemin The hours43).

having

imidazoles, up

deuterohemin

excess

vacuo acid

absence 50% yield

bis-chelated

obtained

purification.

Controlled

hydrolysis

gave

the monochelated hemin 11, again as a mixture of isomers (Scheme 6).

More (obtained prepare and a hemin

recently, from was The series

Molokoedov of yields

et

al.44, ester mixed

have 12 in peptide

used 61%

protohemin yield by 14a-e. using 25%

monobenzyl partial ethyl as Coupling the

ester of

13, to and the

protohemin completed of

dibenzyl by the

hydrolysis),

histidine-containing product

derivatives method 47% to

peptide of

anhydride from

chloroformate length

triethylamine.

decreased

peptide chain increased, the products being obtained as a mixture of the 6- and 7-isomers

125

(Scheme tide 14e This appended derivatives ments, (30-60%) tuted more the

7;

only

the

6-isomers were to 6-

are

shown). to a

The be

reduced for

pentapeptide 35-40 minutes IX with to of of the

14d at

and room 15

hexapeptemperawith two frag-

heme work (a

derivatives was

reported prepare The and or

stable of

ture in chloroform solution in the presence of air. extended of IX in series protohemin condensed methods, mixture that capable chain site c of a derivatives IX various give 6the and having to using is 17, a peptide the fragments45. pentafluoroester 8). Absorption the environment two attempts of of to previously 7-isomers) mixed 15a-i spectra chain the model prepared protohemin monoaminoacyl peptide unsymmetric 7-isomers unsubstiFurtherenhance hemeto to the

mixture protohemin

were as

using

anhydride indicated were bulky the

bisaminoacyl histidine

derivatives peptide

(Scheme

complexes was

residues

pentacoordination. believed c

hydrophobic have been with via His-18

pep ide active The cysteine for of ethyl the

the stability of the 5-coordinate iron(II) derivatives. There peptide be the teau cytochrome the 14 of al.38, chains 17 the active atom et site and the of (Scheme could the c. poor this cysteine to compounds. Sequencing structure sulfide provides with IX of a (16) spectra 17. ligands the various to of he the to obtain of a An to to the the that methyl observed attempt the (TPP) the cytochromes two ligands that reveals heme iron side porphyrin of e.g. residues segment 14-18 bound while

invariant, polypeptide of and

14-Cys-X-X-Cys-His-18. bonds one

imidazole

heme.

Momenprotected

Loock46,

strategy to

similar

Lautsch

attached

pentapeptide iron the then by insertion, metal mimic are covalently

(Cys-Gly-Gly-Cys-His) optical the poor

2,4-a,a'-dib9). bind iron After to would binding of the

romomesoporphyrin centre

appended thioether in was was the

indicated sphere iron. thioether

imidazole

histidine cytochrome

Binding for

methionine, to this overcome case Various a

coordina ion

natural In

However,

thioethers synthetic

made used.

attaching

porphyrin.

deriva ive

porphyrin,

tetraphenylporphyrin

dipeptides

were condensed with the TPP derivative 18 bearing a propenoate ester side chain at a (b-

126

127

pyrrole residue on the

1

position with peptide and

Reaction 19 are and the might

of

a cis-exo in

dipeptide 20 a

containing acid, 10). In

a the

terminal a cis-endo for metal only (R sulfur data be

S-alkvl mixture case, to = a

cysteine of metal two in substituents

cis-meso-tetraphenylporphyrin-3-propenoic cis-endo chain When magnetic residue Zn (Scheme favourable chain was suggested However, disposed

gave

atropisomers, the

conformation that recent a could

binding

porphyrin. cysteine

dipeptide be

Gly-(SR)Cys-OEt EXAFS

Me,

trityl), involving that for long

H-NMR

circular

dichroism occurring. the

bond weak

the the

indicated

substituted

porphyrin,

Zn-sulfur

interaction

and

range, if it occurred at all50.

3. Chelated Hemes
3. A. Porphyrins Having Covalently Attached Imidazole or Pyridine Ligands
Chang imidazole bond51. imidazole would and had On 21 give Traylor either the wi h a the argued too other acid strain-free that or it hand in too of heme-pep ide many was argued 23 models to that XV the achieve 22 side a chains strain-free of by containing the few atoms iron-imidazole of iron heme

condensation followed 11).

l-(3-aminopropyl) insertion "chelated"

chloride

pyrroporphyrin

five-coordinate-system

(Scheme

This

was capable of binding dioxygen in a reversible manner in the solid state or when

128

dissolved -450C, tives the and and of

in only

polystyrene protoring the one 25 and

film.

While

capable at having amide were to a

of

binding or

oxygen

reversibly A

in

solution of For bound

at to 12 The an the or a pre-

irreversible

oxidation ester the then with

occurred or hemes porphyrin coupled excess

room pyridine linkages easily

temperature52. imidazole as was or by by was prepared 24 amine followed then isolated

series covalently in

derivaproto-

pyrro-,

mesoheme

porphyrin mesoheme, 1356. In or 3 The of

through approach was base amine. up

investigated26,53-55. shown partially alcohol one

monochelated

Schemes containing of as

dimethyl

ester primary

hydrolyzed.

purified imidazole

monoacid was

pyridine primary in

using The 30%

pivaloyl pivaloyl 26, yield. 28 reaction

chloride. chloride were mixture The

Alternatively was

commercially equivalent with

available water

protohemin methanol. mixture pared.

treated

base-containing

quenched were

monochelated to

products

chromatography

isomers

dichelated

compounds

similarly

129

The kinetics side

versatility of the the the low 14) at

of O2

the and

chelated CO base,

heme to the

approach these leng h of against a the

has

allowed of

the the

systematic in chelation

study

of

the been

binding and

compounds. and nature

Changes

solvent, arm

porphyrin

chains, Unlike

chelated

have

correlated with changes in the association and dissociation rates of O2 and CO57-58. "chelated-histidine" temperatures, he such binding of the a Traylor to temperatures dimerization IX of the cyanide system argued and design 29, Momenteau42 the used in which of his is and leads vs. underwent any studies26. too binds vice to log dimerizaforms Trayhe allow to tion Ior at presence exhibiting chain While affinity cyanide Y/l-Y (log pyridine polymeric Indeed, For to poorly

(Scheme iron(lll) hemin, titration to the titration centres. Axial ester 32

concentrations side 15). pyridine 29 2.1, to with plot

exploited

system

cooperativity59. short very versa. clean [CN])

protoporphyrin addition of gave base

derivative pyridine greatly pyridine dimer 30. slope

intramolecular

(Scheme increases

Therefore conversion for the this metal

side-chain straight chelation the

protohemin A n Hill =

pyridine-hemin-CN_

line was

of

indicating prepare by two iron rate a

cooperativity symmetric to

between diheme60.

similarly was CO anhydride, with

used

Meso-1,2monomethyl diheme either 33 two

di-(3-pyridyl)ethylenediamine through 16). (Scheme The orientation shifts for published Tabushi heme (22%) stable densation The reaction
1

(31)

coupled followed exhibits of to the the

with

mesoporphyrin give the constants, indicating of

pivaloyl

insertion

environments or a sequential change of environment due to cooperativity. paramagnetic 34 of the for et of and the methyl various al., in have H-NMR were with and heme used the vinyl spectra respect proteins chelated imidazole-cyanide of the of porphyrin ring, these complexes causing shifts for mimic was pyrrole resulted displayed in the the dichelated a fixed values chemical protohemins 35 base studied61. protons. Chelation imidazole maintains different with the

Comparison provided heme

confirmation approach to 37

heme-imidazole of the conas of to

orientations proposed in the natural systems. orientation by groups (Scheme gable cytochrome 17). After 38

c3

62-64

The

"gable-porphyrin" 36 use which with of 39 the

prepared and the

the such

(m-formylphenyl)triphenylporphyrin metal and wi h insertion,

benzaldehyde formation behaviour

dimeric

bridging

ligands

N,N'-diimidazolylmethane porphyrins

g,g'_pyridylmethane bridging ligands

cooperative

the binding of I-MeIm and CO.

130

131

The dimers mate. chlorophyll

H-NMR higher and

analysis converted with 41 42

of it

chlorophyll Denniss to he 18). and by

is and

often

complicated with

by

its he in the

tendency phytyl he imidazole spectra. the A complex

to group

form of

or

aggregates.

Sanders65 anhydride 40

removed resulted of
1

chlorophyll-a

mixed

triethylamine/ethyl

chloroforchelated to the similar formed In

Reaction derivative

l-(3-hydroxypropyl)imidazole (Scheme was used Intramolecular gave Boxer a the 44, well and

binding to

magnesium "chelated

prevented chlorophyll" et al. or

aggregation

resolved Wright of

H-NMR model

when apomyoglobin is reconstituted with chlorophyll derivatives66. Momenteau this ring, to tion series via the the the amide have is ester 45 as gave 47 he in synthesized to linkages derivative a the similar 19). was and series chelated of a by heme of compounds67. Cu(TPP) base attached (3-pyrrole which of cis position Vilsmeier trans tetraphenylporphyrin a Wittig of (70% (TPP) (43)68

(Scheme

formylation

afforded yield and

monoformyl acrylate

elaborated 46. 50

condensation hydrogenathe and corre60%

mixture with

isomers. 48 or

Demetallation, Treatment or 51

saponification acid 49 chloride resulted

propionic

acid

derivative porphyrin

sponding pyridine

l-(3-aminopropyl)imidazole chelated

3-(3-hydroxypropyl)

appropriate

respectively) (Scheme 19). These models were used to study the kinetics of base binding

132

to

4The

and

5-coordinated TPP-acrylic of Cu-TPP using

iron(II) acid acrylic by

TPP69), system acid

and was

also used a 20). nature

to by The of

study Eaton extent the

the et of

transient al.71,72 in the the

oxygenation of

of the

iron(II) carbonmonoxy TPP after photolytic displacement of CO70. same Cu-TPP Treatment acid was chloride 52a wi h nitroxyl resulted nitroxyl, appropriate linkage spinor

labelled

derivatives EPR

52b-f

(Scheme the

metal-nitroxyl

interaction (amide

investigated

varying

ester), and the geometry of the complex (cis or trans). A similar study was carried out on a vanadyl porphyrin73,

133

Collman to the benzaldehyde

et

al.74), position

have of

prepared a (55)

chelated in he hot

TPP ring.

compounds Condensation acetic

where of acid

the a

chain 2% 56. was used

is

attached (53), after with comporphy-

ortho

meso-phenyl

o-nitrobenzaldehyde gave yield

(54)

and of

pyrrole the

glacial

chromatography, with various pounds stannous imidazole 58a-c as

meso-mono-(o-nitrophenyl)triphenylporphyrin mono-o-amino-TPP Collman less and his readily (57) which 21). the colleages merely

Reduction coupled the

chloride chains

produced (Scheme for

substitutes

accessible

"tailed-picket

fence"

rins which are discussed in Sect. 4B. Mashiko et al.75 used the same chelated TPP

134

compounds els for frustrated covalently ligand tem. was These

to by

control c, the

coordination which affinity imidazole of

in of to

mixed iron then

ligand and for

system. imidazole ring a the

Attempts as the rather mixed tail

to axial than

prepare ligands, thioether. amount and

modare By of sys-

cytochrome attaching provided; authors

contain

histidine heme the

methionine

greater the

porphyrin with

stoichiometric lengths

addition prepared

thioether

furnished

six-coordinate

several

complexes

different

various

thioethers. For the Cs tail with tetrahydrothiophene as the thioether, a crystalline iron(II) complex structure determined (Fig. 1). Efforts to were defeated by "head-to-tail" dimerization. (59) (Scheme 22) was obtained and its crystal obtain the corresponding iron(III) complex

Fig. 1. Computer produced perspective of Fe11(C5Im)(TPP)(THT) 59. Adapted from Ref. 75

135

A similar chelated TPP compound 60 was used by Walker to study the effect of axial ligand effect ing a plane of axial orientation ligand ligand on
76

the In (57) to a strain.

H-NMR case In

shifts the a
1

of tail Walker

the was and of and

pyrrole made Benson

protons shorter have to

in used were

iron(III) the monocontainused

(TPP)bis(imidazole)

complexes . bond bound

this to zinc

study

addition, prepare TPP77).

(o-aminophenyl)triphenylporphyrin pyridine

series

derivatives

61a-e

H-NMR

visible

spectroscopy

to study the displacement of the 3-pyridyl ligand by free 3-picoline (Scheme 23).

Condensation porphyrin common 6378). N-I In

of this

57 to of

with the allow

trans-urocanic imidazole was deprotonation yielded

acid to the the

chloride at

(62) the C-4

furnished rather iron binuclear After

the than

chelated the more and 64

case

attached

position addition

imidazolate.
[-imidazolato

insertion complex

deprotonation

Cu(acac)2

(Scheme 24), a poten ial model for he [Cuu2+/Cyta33+] center of cytochrome oxidase.

136

However essentially system.

magnetic

and

EPR

studies the

of

64

indicated coupled

that

the
2+

FeII
3+

and pair (65)

CuII in

centers the to

were natural

non-interacting, et of al.79

unlike used

strongly

[Cuu /Cyta3 ]

Molinaro attach chelated (68) (gave 500C to of ether or (Scheme Goff a

mono-(o-hydroxyphenyl)tritolylporphyrin to the The reacted of to with to may the porphyrin ring via of with did an 65 to not with (71) in the ether and 70 3-(bromoalkyl)pyridine yield. ester condensation was axial a react TTP be bond. reversibly prepare (69), which hydrobromide elaborated base

covalently Reaction of the yield

series

pyridine (65) 67 in

ligands with 40%

linkage. (66) in at

0-hydroxyphenyl-TTP
porphyrin the 25). the The 80C)

furnished 27% low overall

methyl-4-bromobutyrate temperatures affinity. corre(using varying form on imidazoles80. the solvent By in an the effect

porphyrin

butoxy the

cobalt but

derivatives presence

oxygen

enhance forms DMF

oxygen

used

same 72, the

synthetic when chain, the

strategy (65) allowed "tension"

porphyrins dibromoalkane with

appended

Reaction sponding K2CO3 the of length tilting

o-hydroxyphenyl-TTP which, the of alkane gives

imidazole 73 into

Et3N), of or

required

chelated

derivative introduced This was

(Scheme to

26).

molecule have

elongation

iron-imidazole

found

the splitting and shift of the pyrrole resonances in the 1H-NMR spectrum.

137

3.B. Porphyrins Having Covalently Attached Sulfur Ligands

Because cytochrome large heme of the P450 poor have of to affinity usually excess to the of iron(II) of ion. porphyrins solutions to However, the the for of mercaptide porphyrins Traylor81 of has porphyrin in anion, the used models presence the making of of it consisted mercap ide attach metal

concentrations approach for

chelated ligand

covalently

mercaptide without

periphery, excess

available

binding

necessity

external

(Scheme 27). Protohemin chloride monodimethylamide monoacid (74) was coupled to 1-

138

amino-3-mercaptopropane addition CO pound he of 79, dimsyl in CO anion resulted analogous

benzoyl (77) of 80.

ester and the

(75).

After removed was the

reduction the benzoyl

with group, 78. and the

sodium and A

dithionite, addition of give com-

warming mercaptides

formation two complex

carbonmonoxy-mercaptide also of mercaptide

complex as

similar to

containing

masked

prepared

deprotected benzoylthio

Protection

derivative

before reduction of FeIII was necessary because of the reducing ability of mercaptans.

Alternatively resultant
1

protohemin 82 the was CO

was treated

coupled with

with

bis(3-aminopropyl)-disulfide the iron being

(81). reduced

The faster

disulfide of

sodium

dithionite, that the

than the disulfide. Addition of CO then furnished the carbonmonoxy complex 80. H-NMR complexes indicated sulfide underwent intramolecular binding without appreciable dimer formation.

UV/visible band A and (83).

spectroscopy or of

in

DMSO nm) aryl The C6 (57)

solution which was

or

aqueous to

suspension the hyper has or were to after the give iron

showed spectrum

a of

split

Soret

(384/460 series Groh Since

363/446 alkyl and

similar

carbonylated by Collman monochloride obtain, thio the group or the spectra site; iron(II) low-spin

cytochrome P450. "mercaptan-tail" alkyl chain wi h acid to the TrS-K+ thiol. flexible to does lead to to porphyrins may be S-acetyl derivatives porphyrin or hold of the However, been prepared by (Scheme the chain by that in The 28)82. prepared directly treating to the

(oaminophenyl)triphenylporphyrin S-protected was first gave chain were of treatment he alkyl bromoalkyl introduced detritylation indicated spectra, species.

S-tritylthiohexanoyl more 85 difficult and

pentanoic attached either free too

with the was CO

AcS-K+.

Deacetylation insertion, at the

(MeOH/NH3) visible metal

(HgIIZH2S) toluene,

mercaptan planar of

similar

those

square

four-coordinate six-coordinate

introduction

formation

FeII-CO complexes.

To CH3) case quen ly

ensure or the

greater thiol with

rigidity, was sodium

tails

derived 87 as

from were the to

o-mercaptobenzoic attached the to free the 86 or aryl (see

acid 87)

(86; which

= In

or this

(m-mercaptophenyl)acetic potential cleaved

acid

aminoporphyrin. was "mercaptan-tail"

introduced

disulfide give

subseporphy-

borohydride

rins 90 and 91. As in the alkyl case, the aryl iron(II) species did not show five-coordina-

139

140

tion.

Furthermore, on the of

addition nature the

of of

CO the

gave mercaptan to give

mixtures and the the

of

five-

and

six-coordinate suggesting a The

species, tail-off/tailextent of

depending

temperature, was

on equilibrium. Deprotonation mercaptan mercaptide attempted. mercaptide formation depended both on the nature of the base

and for was

of the

the

tail. and a 3.A.

Indeed, complete

for using

most

tails tail

only system anion

incomplete 92, as base. complex

deprotonation to In 93 the

occurred. the of visible (59) as of in

However mercaptide CO this spectrum a model of tailed 60-90% base easy effective

(m-mercaptophenyl)-acetamide gave six-coordinate we c .

75

deprotonation

clean

acetanilide

presence whose

system In for attaching porphyrins (Scheme allowed

iron(II)-mercaptide-CO to the and to the the synthesis of

exhibited a split Soret absorp ion at 450 and 380 nm, typical of cytochrome P450. Sect. the referred ligand with FeII(C5Im)(TPP)(THT) adopted the 94 periphery83. anhydrides or R2SO precluded sulfone > R2S this cytochrome Buckingham 57 iron by Rauchfuss porphyrin sulfoxide, reduction, affinities: imidazole corresponding and ligand or alternative Reaction afforded groups titration > system R2SO2. as strategy the with The an

thioether

(o-amino-

phenyl)triphenylporphyrin 95a-c, 29). the of After following sulfide

containing ordering

thioether, of

insertion pyridine

spectrophotometric

displacement

model for cytochrome c.

141

Smith P450

and

Bisset but A the chains. the followed which to dithiols in

have this

also case

used the

the

chelated substituent leading of

heme is to

approach to ready in the give susceptible the 96

to the

synthesize meso to

potential of an dissuitably 1,6-hexto he the mesorefluxmeso-che98,

model84, at

substituents atom sign with by

were

attached

position of

octalkylporphyrin. placement anediol the functionalized gave of bromide

meso-acetoxymethyl "benzylic" Heating 97 by was 99 ether carbon the with no

nucleophilic with salt 99. 100

introduction a melt 30).

acetoxymethylporphyrin dimer oxidation thiourea afforded to

formation

(Scheme the

Conversion

refluxing the

thiouronium disulfide of of

hydrolysis nately, disulfide phyrins ing

accompanied were

Unfortufrom

attempts complex with

generate yielded

characteristic only the excess of

RSFeII-CO

spectrum treatment

unsuccessful. with a

Alternatively,

acetoxymethylporof in the 21

meso-methylporphyrins. sodium hydride

Treatment provided

acetoxymethyl

octaethylporphyrin containing

l-(3-aminopropyl)imidazole

tetrahydrofuran

suspension

lated imidazole porphyrin 101 (Scheme 30), a potential model for T-state hemoglobin.

The success of the chelated heme approach to model heme proteins is due to its ability to tion control and the coordination covalent binding e.g. of ligands Addition of a metalloporphyrin. to the of the need of For excess chelation base to poorly external can an iron binding the used porphyrin ligand. be ligands local In to the e.g. case in merof their a captide, strongly binding thioether, enhances binding ability. attachment without one imidazole, porphyrin increases concentralower results

pyridine,

equivalent

mixture of four- and six-coordinate species, since K2 > K1 in Eq. 22.

142

However equivalent

covalent of base

attachment which

of can

the bind

base

to

the

porphyrin to give

provides the

stoichiometric five-coordinate

intramolecularly

desired

species, provided dimerization is not significant.

Such model

an

approach

has e.g.

been

followed

by

many

groups cyclophane

to

produce and

an

array

of

different and

porphyrins

picket-fence,

capped,

crowned,

strapped

basket-handle systems.

3.C. Porphyrins with Covalently Attached Quinone Groups

An have approach, similar to interest where earliest 103 of to that prepare as of the chelated with models charge was that heme for model the systems, quinone from Loach a has been transfer adopted event by of state mesodesired Mcintosh of the these electron to an many researchers stimulated porphyrins possible appended groups. excited who Such singlet a systems

primary occurs and with

electron

photosynthesis, One of the

photoinduced such models (102)85. by

transfer of

chlorophyll donors to nearby quinone acceptors. Kong and 105 = prepared he by nature that which chain (p-carboxyphenyl)tritolylporphyrin dime hoxybenzene A et linkage transfer similar who (ester followed Condensation demethylation tritolylporphyrins laser = 3), quinone; flash could suitably furnished prepared and the in the indicated substituted

oxidation have 2, a been 3, 4) studies

porphyrin-quinone pair 104 (Scheme 31). series varied or substituted the EPR (a, b; al.86-87*, both 105 length of and n to the chain (n

amide). from

photolysis adopt

compounds,

especially

conformation flipping of

occurred

porphyrin

subsequent

extended conformation could then prevent recombination and lead to a long-lived radical

143

ion lar of

pair.

Wang rings

et with have

al.88', to an

prepared the appended

series

of

porphyrins by were lipid

106,107 amide also

having

either (Scheme and

one 32). both

or

two Simi-

quinone

attached

porphyrin

periphery group bilayer join and into to

linkages prepared,

porphyrins compound The use

carotenoid

classes in can vary.

been or the

incorporated ester the linkages

membranes. and the

Photoconductivity quinone moieties can of quinone later

such membranes was enhanced relative to simple membranes89. of amide as to more the porphyrin of lead to complications solutions use of both separation of to orientation two centers and and

Possible (i) the

problems spacers and

porphyrin-quinone separate strapped ion the

orientation porphyrin are

prolonging (models in the onto

the change-separated species have included: rigid strapped the employing (ii) attempts capped, to doubly quinones pair by described other

appropriate sections); stabilize transient radical introducing groups the porphyrin.

144

Tabushi chloride in observed extended tion TPPBQ the tively). of (108), which

et the but

al. which, no the 110 111a.

have after

reacted selective was

mono-o-amino hydrolysis is proposed. fixed in and reaction TPPAO and Hlc and fixed. The

TPP oxida ion, Efficient

57

with

2,5-diacetoxybenzoyl 109 distance (Scheme quenching has 34)91. the 18% 33) was been Reacproduct of rate respecThe

furnished

porphyrin-quinone mechanism relative (25%). TPPNO

distance

fluorescence llla-c yielded prepared (15% 10.5 and for

porphyrin-quinone pyrrole with were at 10,

and

orientations Diels-Alder Illb with distances charge and

compounds

(Scheme gave by and 11

2-anthraldehyde,

benzaldehyde

meso-(2-anthracenyl) condensation

triphenylporphyrin (40%) The corresponding for

benzoquinone

2-aldehyde

pyrrole were

benzaldehyde and

porphyrin-quinone photoinduced

estimated

A.

constants

separation

recombination

these

compounds

have been reported92. The condensation of a linear tetrapyrrole 112 and an aldehyde to

145

form The

mesosubstituted (Scheme 35) bicyclooctane

porphyrins with yields units

was

used flexibility

to and base

prepare only and

another distance rotational

series (6, 10 freedom

of and is

compounds 14 an with the ylide free order may

113-115 Preliminary A systems substituted porphyrins showed in which

increasing of the of which the double The rate

porphyrin-quinone free

)93.

eliminate

allowed. increthe meso11794). base to thus systems prepared96

fluorescence

zinc

porphyrins was

indicate observed of the in In was and

mental effect of distance on photochemical electron transfer93'. similar shown incremental in Scheme 116 of 119a, effect 36 (as the b. porphyrin-quinone were nickel bonds of on the a prepared complex) and the then separa ion by Wittig the with condensation phosphorus furnished transfer the 120 chain95.

porphyrin reduction and inverse a the pair 118

Deme hylation, an

oxidation electron of

photoinduced

such

exponential electron quinone of

dependence transfer rings

length

demonstrate

multistep

bis-quinone redox

porphyrin potential

provide

gradient

stabilize charge separation. Comparison with the mono-quinone etioporphyrin 119a

146

showed the is for much the

approximately time longer was than of

exponential much for 120 to A was

decay for

of 120.

the he

charge

transfer of Moore

state the et both the

in

both

cases, in in and to

but 119b 120 a the

decay

longer

Similarly

photoinduced

charge second al.97, a was

transfer quinone used quinone

demonstrating prepare a by

importance states. separated

generation group

long-lived

charge-separated system charge electron

5,15-bis(4since

aminophenyl)-bistolylporphyrin carotenoid charge 121. recombination

incorporating transfer from

photodriven inhibited

complex

observed

porphyrin cation radical, to give a long-lived (us scale) C+ -P-Q - species.

carotenoid

3.D. Porphyrins with Covalently Attached Interactive Groups

A than and tion variable number of o her have 122. the "tailed" prepared Both porphyrins a series and the have of been or derivatives EPR terminal prepared which a contain groups other Maiya chain the of tail to interacpotential Krishnan98 length between Similarly a cyclodextrin 123 did While ligands. Using mono-(mand p-hydroxyphenyl)triphenylporphyrin, containing data group, was guest phenoxyglycol intramolecular that suggesting covalently oxygen in inclusion indicated

fluorescence ring

porphyrin

phenoxy (65) a

existed in a folded-over conformation. mono-(o-hydroxyphenyl)triphenylporphyrin unit, not in the display hope the of preparing desired attached carrying the water-soluble model99.

properties,

cyclodextrin

moiety appears to induce novel conforma ional changes in aqueous solutions.

147

Other

cyclodextrin included of a Fe11

capped in an

hemes

have

been which

prepared101 formed oxygen porphyrin could a

using

1-substituted

2-mecomplex exploited Covalent

thylimidazoles with protoheme. The by the Lown 124a-c series and ability of

a-cyclodextrin to generate to

pentacoordinated has deliver rise an to been the DNA A a

porphyrins prepare DNA where

reactive an of iron

radicals might give with

several DNA and of

groups

to

systems reactive a of

with

potential species

antitumour

properties.

attachment

suitable surface

intercalator

heme

to

helical

oxygen series the

scission. acridine similar spermine

Joshua101 mimic in

have the a

prepared properties 125,

deuterohemins from

attached

which

glycopeptide is bound to

antibiotic the

bleomycin. via

compounds which

126,

derived

mono-p-aminophenyl)-tritotyIporphyrin porphyrin

protohemin,

suitable

intercalator

chain, has also been prepared which exhibits oxygen-dependent DNA cleaving ability102.

148

4. "Picket-Fence" Porphyrins and Related Species

4.A. "Picket-Fence" Porphyrins
Perhaps porphyrin (i) due the of to most successful Steric of the heme protein about adopt to the a active metal site site models of in is these which the "picket-fence" TPP mesoat the and, Collman. steric rings encumbrance the TPP will substituted the four

molecules depends on two factors: repulsion, are conformation the porphyrin phenyl phenyl (ii) for essentially perpendicular ring; substituents separation the four

orr/io-positions of the phenyl rings will lie above and below the porphyrin plane, and TPP molecules on the that containing bulk of mono-ortho-substituted the of the thereby subs ituent, a same could dioxygen could groups and four rings, of depending Collman four could of bered stable "protected not and since excess interconversion iron(II) the the metal possible having give face a but

atropisomers may be achieved. reasoned groups pocket". ligand. a the of the (4a, was 3ab the syn hesis on e.g. much substituted side bind of to tetraphenylporphyrin ring the in be would open the sterically oxidation on even not pivalamido located porphyrin

Ligands the The bulky

imidazole, smaller complex

penetrate

pocket,

ensuring form. should

five-coordination would This

presence encumbe through (53) in four moving was

molecule

six-coordinate

oxygenated

complex

should

pivalamido (55)

prevent of

irreversible

close approach of two porphyrins and formation of a u-peroxo complex. Condensation acetic chloride atropisomers of which acid to gave pyrrole equivalents 128 by o-nitrobenzaldehyde was reduced 37)103,104. the the of by The slowest meso-tetra(o-nitrophenyl)porphyrin 2a2b) were separated 129. which stannous

meso-tetra(o-aminophenyl)porphyrin desired aaaa isomer

(Scheme

chromatography,

Interconversion

atropisomers

sufficiently slow at room temperature to afford clean separation. Refluxing the unwanted

149

products further gave frozen zation the by of

in

toluene of

for he

20 aacta

min

effected

reequilibration of the on

to amino

the in

statistical with the which with

mixture pivaloyl and

allowing chloride is by isomeri-

isolation the these

isomer.

Reaction

groups

"picket-fence" bulky

porphyrin substituents.
II

a,a,a,a-H2(TpivPP) Several been studies made105-107'.

130, the

configuration followed

physical

properties FeBr2,

atropisomers

have

Treatment

reduction with Cr(acac)2 gave Fe (a,a,a,a,-TpivPP) 131.

Although "picket-fence" compounds pyridine, reversible amounts

addi ion side was was

of it

strong was less (B than

field that Im, in

ligands that on the

gave the

low

spin constant A All 25

six-coordinate of the of series of C,

complexes, on the six-coordinate l,2-Me2Im, showed appreciable (N-RIm)(O2)

FeB2(a,a,a,a-TpivPP),

suspected =

binding "open" l-n-Bulm, solution

base

side.

prepared binding

l-Melm, benzene the

l-trityllm, at

4-t-BuIm, these without

piperidine, oxygen of

tetrahydrothiophene, behaviour Indeed,

tetrahydrofuran)104. oxygen

decomposi ion.

complexes,

Fe(TpivPP)

were stable for long periods (ty2 2-3 months) in solution provided 2-4 equivalents of axial

150

base talline

were

present

to

protect 132a

the could (Fig.

unshielded be 2)104108,

face.

Furthermore, The

analytically crystal EtOH

pure, (Fig.

crysof 3)

dioxygen

complexes

obtained104.

structures

Fen(TpivPP)(I-MeIm)(O2)

Fe"(TpivPP)(2-MeIm)

and its dioxygen adduct109 (Fig. 4) have been determined. Further structural information

Fig. 2. Perspective view of Fen(TpivPP)(I-MeIm)O2 (132a). Adapted from Ref. 108

151

Fig. 4. Perspective view of Fe(02)(TpivPP)(2-MeIm). The dioxygen and imidazole are disordered. The disorder has been idealized and only one concentration is shown in this figure, which is adapted from Ref. 109

152

was also

obtained been Binding

by

I.R108,110,111 The reversible Reviews

and on

Mossbauer of oxygen binding

spectroscopy to to cobalt picket side

and fence, of heme under the

magnetic of and

susceptibility TpivPP has systems prevented However, give O2 (B the and Similar = that

measurements82'108*.

binding

oxygen

complexes

studied112. of of a

related

have also appeared32-37 113-115). second oxygen base binding could on to could be the the be "picket-fence" porphyrin solu ion. to between cycles116. was region the to of Fe(TpivPP)B it regions of of determination crystals vacuum reversible 2-MeIm, solid tive on state binding of five-coordinate five-coordinate deoxygenated oxidation solid and a are in the Y vs. an re-oxygenated. by Y/l in

FeII(TpivPP)(I-MeIm)(O2) species no From binding and iron rationalized as the of the high which was the for low this and observable Hill

vacuum many of

This over log samples

cycling

produced l,2-Me2Im). oxygen (at

irreversible plot (log two terms bound the

oxygenation

demonstrated these O2 in its in

P0z) two

concluded

compounds of solid strain

showed

non-cooperacooperative dimensions ring. As molecular conformadeoxy condenchlorides. H2(TTOSPP) p-toluenesulthe ferto exposure and been

pressures)

intermediate of the this towards

binding. increasing

Collman numbers in

shrinking move

molecules' porphyrin in a change induce the

oxygenation

imidazole

molecules induces solid which

oxygenated the crystallite affinity been with

dimensions tional

presumably

sufficient

change

enhances TPP

oxygen have 129

remaining by the

sites. This behaviour is reminiscent of the cooperative oxygen binding of hemoglobin. Various sation Collman (136), fonyl rous oxygen directed quent The yielded be CH3I, para by of et other al. reaction 134 of
0

sterically have of

hindered

derivatives the with 38). the of with a to

prepared bulky (135) 133

meso-a,a,a,a-tetra(o-aminophenyl)porphyrin also prepared (129) (Scheme to H2(TAmPP)

acid and and on were

compounds, iso-phthaloyl Despite only acidic of TPP

H2(TphthPP) dichloride bulky protons the

chloride complexes at heme 25 into

respectively both This cavity, A was

"picket-fence", which

compounds attributed similar allowing

exhibited protona ion series (129) as

irreversible amide the

oxidation

presumably consesyn he-

the

coordinated

dioxygen have chloride hen The potentials, ligand of

oxidation104*. of

derivatives

137a-g

sized under identical conditions by Bogatskii et al.117-118. reaction the by by o-H2(TAmPP) TPP excess isonicotinic of groups the and used For water 39). reduction as were hydrochloride which could with tetra-isonicotinamide anion statistical yield mixture atropisomers soluble

separated followed and

chromatography.

The

isonicotinamide (138)

methylated

exchange, were also have

tetrakis-(N-methylcorresponding basicity systems and by

isonicotinamidophenyl)porphyrin-tetracation meta deriva ives TPP

(Scheme

prepared been

reactivity with metal ions of the isomers were compared119. Ort/iosubstituted choosing suitable derivatives on the binuclear substituents phenyl rings. example, treatment a,a,a,a-

H2(TAmPP) 129 with maleic anhydride gave the tetrakis(o-maleamoylphenyl)porphyrin

153

(139) insertion the

in at copper

90% a by

yield rate the

(Scheme much faster carboxylates capable the

40). than holds of

In

aqueous for the metal iron of

DMF ion and in

this a

porphyrin Rapid position have

undergoes favourable for

copper of rapid as 141

unsubstituted

porphyrins.

complexation

intramolecular transfer to the porphyrin nucleus120'. Binuclear synthetic porphyrins for binding site copper been One inves igated model models iron/copper cytochrome oxidase. such

consists of a tetraphenylporphyrin ring with a covalently attached tetrapyridine ligand

154

system, (140) ring and claim tion tions and

obtained (Scheme copper the

by 41)121.

treating The to of

a,a,a,a-H2(TAmPP) metal four for the compound the the

(129) with

with iron In

excess inserted was contrast,

nicotinic into Elliott cause Ru" the and

anhydride porphyrin the and to EPR Krebs the condimetals

mixed

coordinated conditions

nicotinamide metal insertion these divalent into

groups into place and

prepared, complex more

magnetic that of to the be

susceptibility nicotinamide

complex Instead, of

examined12'. authors

necessary groups123. locks the

this have

isomeriza-

coordinated first-row

nicotinamide

groups, used

which for

"pickets"

allowing

forcing transition

introduction

trivalent

into the porphyrin ring, without fear of isomerization.

155

Iron oxidants have chiral strate

porphyrin is believed the the

catalysis to catalytic porphyrins iron-oxo with group was The was (142)

of

epoxidation via a

and

hydroxyla ion of olefins of

using using were

iodosylarenes and of by was group cavity acid iron 20-50% 42). suitably

as

proceed to

reac ive the The chiral

iron-oxo

intermediate.

Groves

Meyens suban

attempted olefin to

asymmetric control species124. an as in the the

epoxidation chiral active

substituted the With reacting formed was about (144) insertion. were

"picket-fence"

stereochemistry porphyrins acid of the various Instead and by

approach prepared 143a with chiral and of (Scheme

a,b,a,b-H2(TAraPP) in very chosen the was This high little as yield an

optically

chloride

(R)-2-phenylpropanamido (95%). selectivity core. with 143b

appendage 9-31%). a large of followed

porphyrin olefins the rigid

However, which

epoxidation form

iodosylbenzene

obtained could diacid -H2(TAmPP) more

(%ee, chloride (142),

binaphthyl

appendage

relatively

porphyrin reacted catalyst

l,l'-binaphthyl-2,2'-dicarboxylic methanolysis excesses enantiomeric

a,b,a,b

efficient

and

observed for variously substituted styrenes and aliphatic olefins.

156

More ence ence of of

recently HCl acid to its

Tabushi as

et a and

al.125 cytochrome slow pickets However, phenyl

have P450

used

oxygenated on Under ferric of

Felll(TpivPP)Cl conditions followed has

in in by been are

the he

prespresis

and

H2-Colloidal

platinum

supported mimic. of the

poly(vinylpyrrolidone) such complex the that ring this

chlorides

cyclohexene

converted A with

epoxide 145 =

reduction on

formation prepared substituted will be a

of the dioxygen ferrous complex completes the catalytic cycle. porphyrin 43; R' the bis-ortho bearing CH3)126. both so it faces is (Scheme only two opposite unlikely meso-positions

substituted

rings

compound

successful oxygen binding model.

4.B. "Tailed Picket-Fence" Porphyrins

While solid base prevent is complex the state, direct such oxygenation studies in To to in the control of five-coordinate were not of presence FeII excess on Collman "picket-fence" since sterically the et "open" al., the was observable base. prevent the in the not solution complete possible "picket-fence" face and could

six-coordination necessary formation.)

unhindered adopted

(Excess (-oxo "chelated

ensure

coordination

coordination,

heme" approach. Dispensing with external ligand, the base was covalently attached to

the

ortho-phenyl

position to

of the

TPP, porphyrin (129) 146 free to were

and

so

constrained The other

into three of

position

promoting rings gave a and carry he solu(3 aor vary-

intramolecular Treating "3-picket" tion for 2

binding

metal. with (35%) 3.2

meso-phenyl chloride in of (The by the Using

the "pickets" necessary to prevent irreversible oxidation. a,a,a,a-H2(TAmPP) a-aminophenylporphyrin h equilibrated 146, be an 147 the which was equivalent 44). to of a group by yield 149. the pivaloyl Refluxing 1:1 the mixture b-product.) 147 iron(II) (due 25 to in insertion (Scheme benzene unwanted amide of chains using "tail C) a

aminophenyl separated the to and of increase 148 spectra but on were had

atropisomers isomer urea ing FeBr2 spin to a (S could linkages leng h gave =

chromatography.

re-equilibrated imidazole the

attached yields

he

P-aminoporphyrin Direct the the metal five-coordinate

to e.g. 2)

yield nearly iron(II) (S

porphyrins
1

anhydrous picket-fence" high due peaks

quantitative H-NMR 0) not formulation, = but

porphyrins,

15174.

confirmed decreasing observed, observed

proposed

five-coordinate

temperature presumably such

diamaenetic

complex Travlor.

dimerization the chelated

Drocess.

(Momenteau.

dimerization

heme systems.)

Addition the peak plexes, A pyridine The and Sect. fence" thioether aryl

of

oxygen spectra for the

to of

solutions a "pickets" the

of

the

high that of

spin the the

five-coordinate for the a may be

iron(II) ordered

compounds species in which 151. these is

gave The com-

expected pattern

diamagnetic suggests open side

compound

oxygenated suggestion has urea been

oxygen pocket,

presumably similar

towards of

awaiting with and of of a CO alkyl in the

confirmation by X-ray crystallography. series "tailed to picket-fence" the porphyrin porphyrins periphery 57 P450 been the 150 via to synthesized O2 covalently use 3.B. A of attached linkages127. a by

binding to both series of porphyrins has been carried outl27_l29. meso-(0-aminophenyl)triphenylporphyrin porphyrins series of as 147 45)82. prepared cytochrome has give A and similar is to similar 154 also compounds prepare has series acylation "tailed an reversibly with of mercaptan-tail models alkyl been described

prepared 155

tripivalamide-|3-aminophenylporphyrin porphyrins chain has (Scheme been

mercaptan capable

picketappended binding

compound reportedly

dioxygen74.

5. "Capped" Porphyrins and Related Species

5.A. "Capped" Porphyrins
The rins direct was a condensation exploited by benzene tight On that the which probably "cap" to porphyrin. ring the other should to a result give Unlike of was aromatic and aldehydes co-workers to to attached bases on the smaller a physical a low and all pyrrole four to form tetraphenylporphyIn the these mesobe fit It of Baldwin prepare "capped" porphyrins.

molecules was nate under was linkages attached the rin ring

covalently of the

or//io-positions

phenyl rings, enclosing a volume of space above one face of the porphyrin ring. If the cap sufficiently on the species. the recognized would to the binding face; hand, (e.g. open alkylimidazoles, face to would [x-oxo a the molecule with pyridine) result would in be by a should able four units to the to prevented enclosed binding five-coordi-

dioxygen barrier ring was

cap,

provide in the

complex porphyrin with necessary of

formation.

attempts

condense very

benzene yields. which

ester were give is

Instead

tetraaldehyde

condensed

pyrrole

"capped"

"picket-fence"

porphyrin,

cyclization

porphy-

is the last step of the

synthesis, so chromatographic separation of

atropisomers

not required.

The with 159.

required of

tetraaldehyde to the yield

156 158,

was with

prepared by pyrrole in

by

alkylation refluxing

of with

salicylaldehyde pyromellitoyl acid yielded

(157) chloride the

bromoethanol Reaction

followed

condensation

tetraaldehyde

propionic

"capped" porphyrin 160 after chromatographic purification (Scheme 46) (Fig. 5)130,131.

Fig. 5. Two perspective views of the "capped" porphyrin 160 as the free base. Adapted from Ref. 140

The

same

reaction

sequence or

using

2-(3-hydroxypropoxy)benzaldehyde porphyrin the on 161 extra he in which there

yielded is an

the extra to

corremethythe

sponding was larger

"homologous" lower To (5%),

"C3-capped" probably steric

lene group in each link of the cap131. In the latter case the yield of the cycliza ion reaction much cap. reflecting hindrance entropy uncapped factors face required a form provide "naphthyl-C2-capped"

porphyrin 165 was similarly prepared (Scheme 47) from 159 and 162 via 163 and 164131.

Inser ion crystalline containing

of

iron axial

into base

the the

"C2-capped" spin iron(II) five-coordinate

porphyrin, porphyrin heme

followed 166 was formed

by

reduction, 46). was In

gave capable

a of

four-coordinate excess

high

(Scheme

solutions

which

reversible dioxygen binding at 25 0C The stability of the dioxygen adduct depended on

the axial that side

nature base, they of

and the were a

concentration Unlike larger small, the size e g., of

of the

the

axial

base

and 166

the which

position could of two bases iron,

of only axial

the

equilibria a

in

Scheme

48130.

"C2-capped" propylamine. could binding was

porphyrin For still

bind bases, as a

single provided it the

"C3-Cap" weakly

permitted coordinate reported

binding size to to

intermediate

such

l-Melm, through

appeared

that the

second

base

the

probably

cap.

Oxygen

occur,

giving

pseudo-seven-

coordinate complex132-134).

The been natural

O2,

CO -

and . It and

NO

affinities found

of

series O2

of e.g., >

FeII the

and were Fe"

CoII much

capped lower (167)

porphyrins than of > those

have of >

studied

131 137,l38

was other >

that

affinities

porphyrins

synthetic

models (160)

complexes

H2(TAP)

H2(NapC2-Cap)

(165)

H2(C2-Cap)

H2(C2-CapNO2)

H2(C3-Cap)

(161). In contrast CO bound more quickly than O2, and the rate of binding was indepen-

Fig. 6. Perspective view OfFe111Cl(C2-Cap). Adapted from Ref. 141

dent

of

the in

cap terms

size of a (Fig.

and steric too 5)140

comparable effect small in of to and exist

to the

unhindered cap. (Fig. the

model the 6)14

porphyrins139. crystal or that O2, a system However, of the

This of the

was both phenyl be bent

ra ionalized H2(C2-Cap) cap-porphyrin more Fe-O-O

Although either

structures

(160)

FeIIICl(C2-Cap) solution. against by a a

indicated CO Fe-C-O effect. effect

separation version under might

was must cap be

accommodate That "central"

considerably could the

expanded system

linear steric steric

accommodated chain linkages.

the

argued

destabilized

"peripheral"

methylene

Studies142,143 used to deduce > NapC2-Cap

of

the the >

paramagnetic C3-Cap,

shifts which

in

the The

H-NMR the

of

CoIICap size was

porphyrins in the affinity a

were order of mod-

cap-porphyrin

separation.

relative with been is

cavity

C2-Cap the

correlates has

relative to

oxygen prepare to two

the iron(II) "capped" porphyrins. Recently144 ified "capped porphyrin porphyrin" in which approach a extended "C2-capped" pyridine covalently bound opposite

meso-aromatic rings of the parent "C2-capped" porphyrin, forming some kind of "strap"

(see lowed

Chap. by

6) were

over

the For

porphyrin by solubility with

face reasons the

opposite of it a was

to

the

"cap". to

Bis-amino with benzylate diacid

"C2-capped" pyrrole the folamino Both

porphyrins functions

prepared

condensation

dinitro-tetraaldehyde necessary 3,5 pyridine

reduction. before

condensation

appropriate

compound.

of the corresponding iron(II) C2-Capped strapped porphyrins 168a, b exhibit reversible

oxygen of not low that the

binding

in

toluene (the complex

solution 168a the

at is strap for

room several and

temperature 168b cap has a months).

and t of

show several

good days

stability while

to that does a

autoxidation result affinity of

reactions in of of of a a

C5-Strapped

complex

C4-Strapped -oxo the the

Furthermore, dimer of of 4 locks the binding on

decomposition formation.

complex,

preventing Comparison has a a factor by of

Although values shows

kinetic study has not been made, it appears that the stability to autoxidation is due to the iron(II) strap complexes complex decreases interactions. configuration The to the the The dioxygen. (which O2 affinity also the O2 for P affinity) the the metal of with that iron(II) C2-Capped (166) low

introduction combination complex porphyrin metal more tic in offers steric

C5-Strapped unoxygenated towards to the the

complex 168b, and by a factor of 40 for the C4-Strapped complex 168a. This is due to a steric domed presence resists the the of the and the the cap of the metal porphyrin which the movement strap of

upon

oxygenation. further may

presence

pyridine the This

resistance motion of

movement

oxygenation. and

Furtherbe

interaction

occur

between pyridine

pyridine

side-chains

meyo-aromawould

rings

preven ing

towards

center.

more severe for the shorter C4-Strap, resulting in lower dioxygen affinity.

5.B. "Pocket" and "Tailed Pocket" Porphyrins

To rin is the ide prepare et to approach used to can only by only of a al. to system have which used a discriminates a series of at against of one Fe-O-O bending (129) under The of was with high volume the "pocket" leaving the the face unit binding of CO and As relative the but in above, Oxygen open of he than side. linear one 49). afforded was a may to that of O2, ring it is within monoxunit of Collman combina ion "picket-fence" of an and/or the open toward tilting "capped" this porphy-

prepare steric three be

porphyrins145.l46.

benzene case bind Fe-C-O equivalent the

provide

encumbrance of the bent by

porphyrin, side. the

linked

raera-phenyl accommodated

groups,

pocket

orientation

Carbon

leading to decreased CO affinity. Treatment pivaloyl with choice a of porphyrins irreversible a,a,a,a-H2(TAmPP) formed tris-acid in good A chloride the yield and similar chloride the 170 sligh ly dilution of single the to more 169 chloride benzene 171 acid "mono-picket" (>60%). porphyrin (Scheme conditions pocket picket Condensation pocket by the against

dictated protection the

presence strategy

provided prepare

oxidation.

employed

"tailed-pocket"

porphyrins 172. However, in these compounds, the remaining ortho-ammo group is used

to attach the base, leaving no protection on the open face of the pocket. In contrast to the "tailed For the Piv) tration nant were similar size picket-fence" the of the ranges species. iron(II) the from porphyrins, "pocket" 171a be O2 While a model these porphyrins, five size complexes the undergo rapid state spectral in the of data oxida ion the iron of was to the -oxo on complex145. coordination and MCD even showed the both in CO Since depended that excess he the effects to the pocket. and and the reduced Visible remained large CO O2 CO the absorption showed Fen(Pocbase. concendomi"pocket" were steric porphyrins

derived

coordinate pockets within of for which

presence iron(II)

Although

medium could The

increasing and were and was

six-coordination, "picket-fence" similar, solvent attributed

determined

five-coordinate "pocket" systems electronic affinity

binding affinities affinity.

compared147. showed he two in

porphyrins

systems,

reduction

hindrance of the cap which distorted the Fe-C-O unit from linearity.

5.C. Bis-Pocket" Porphyrins

Eventual occurs this, steric the irreversible because bulk for but the (where steric the ring. would (P2-) oxidation TPP of both is the have protected s ill the be to dianion by "picket-fence" only on one been pocket and side be by of of By axial two have the the the "capped" molecule. on metal prepared both and the choosing bases porphyrins To he avoid correct sides of thus hemes or trisubdiatomic encumbrance present a

octa-ort/io-substituted ortho The porphyrin

complexes could

prepared. may

substituents pockets a barrier the

formed

penetrated approach Vaska of and

molecules stabilizing FeII(P)

form is

close of

centres,

oxygenated

porphyrin.

Amundsen

tetrakis[2,4,6-tris(methoxy)phenyl]porphyrin appropriate

tetrakis[2,4,6-tris(ethoxy)phenyl]porphyrin)

condensation

stituted benzaldehyde with pyrrole148. Balch has shown by 1H-NMR that although the

or ho-methoxy ature role prepared in reduction sterically which natural was he However, binding site. Covalent to by 175 prepare Lindsey was by gave

substituents to Suslick the form and propionic base, of

prevent Fox149, acid

-oxo and who

complex

formation, A

oxidation more in 1%

at

room

temperwas pyrand the

0

proceeds refluxing

FeIII(P)OH to

Fe111(P)Cl11. condensed the species 173 a

hindered yield. yield.

complex with of 30 and of be Metallation

2,4,6-triphenylbenzaldehyde in in to 80%

obtain iron(II)

porphyrin gave to

four-coordinate completely affinity is

Addition iron(II) at

hindered capable

1,2-dimethylimidazole, reversible very which to low was the a a

five-coordinate non-polar model the of other

complex C the the used the

oxygenation compared attributed four

solvents

oxygen an

complexes nature also was

systems,

observation of a

non-polar TPP an may

attachment porphyrin and

group to rings

orr/iopositions structure. Such 10 was

complexes the two

having was of and high the

rigid

approach system The of yield in

adopted

Mauzerall150 by The at

prepare

cofacial to 174, of for

porphyrin-quinone be

separation H2(TAmPP) reaction porphyrin bases (Scheme porphyrin gated and mated151.

between prepared (129). were after

estimated the yield desired groups

where

quinone-tetraaldehyde with of the of a,a,a,abase Schiff yield zinc estiinvesti"capped" the the was the Schiff

alkoxylation reversibility for the room yielded of The the for

fluoranil

which the

then nature 85%

reacted

intramolecular reaction; h. and 24

responsible stirring NaBH3CN Acetylation 177. rate

temperature amino electron

Subsequent metal of

reduction 176

with 50).

porphyrin-quinone properties this porphyrin

80-95% were

insertion to

furnished quinone

quinone he

photochemical

compound

constant

transfer

from

6. Strapped Porphyrins
The which formed strapped some porphyrin group is thus The class usual allowing pagoda, of heme linked synthetic great protein to two strategy versatility models corners has in he The is will to embraces (usually to types tie of all the those strap may face compounds opposite) to be of an made singlythe of in a covalently diagonally

porphyrin

macrocycle. porphyrin, crowned,

been

already (e.g. or

structures

cyclophane, (i) (ii) (iii) Simple Straps

basket-handle, alkyl chains

etc.). role

porphyrins span one

doubly-strapped and may be classified according to the nature of the chain: non-functionalized incorporating straps the or to whose porphyrin, discouraging -oxo bridging and providing a more hydrophobic environment. some which metal at form bulky group which some provide more steric of be encumbrance to or than a simple alkyl chain. Functionalized interacting with five-coordina ion incorporate the group These capable may ligand binding used to L-M-L', porphyrin core. mixed maintain where

six-coordinate

systems

one ligand binds poorly to the metal.

6.A. Non-Functionalized Alkyl Straps

A number of research groups have reported the synthesis of simple strapped porphyrins. Ogoshi et al.152-154'condensed long-chain diamines with a difunctional etio-type porphy-

rin

178

in 51).

the On

presence the of

of

isobutyl 179 of (n

chloroformate = 6-10, axial to absorption

and 12) in

triethylamine 20-30% he it

under after was to was

high claimed the II side or 184

dilu ion that,

to for por-

obtain short phyrins used yield ester yield. to

the straps, at the

strapped binding iron(II) 15 same

0

porphyrins basis a

yield strap

chromatography inhibited, ferrous et (180) in chains in the giving al.135' with 25% by good ferrous oxidation strapped P450 by

(Scheme

visible bulky

spectroscopy under oxygen the -oxo of the

second in

ligand of

five-coordinate

species. resulted

Attempts rapid high the

observe

binding

forma ion bis-acid to of dilution by

complex.

Battersby 182

strategy, (181) 52).

reacting under

chloride give the

mesoporphyrin porphyrin coupling 183, to an as carboxyl

1,12-aminododecane (Scheme or amide gave the THF in ferric 185a to 185a has natural steric were benzene.

bridged oxidative

Alternatively, the strap or ester-, can aqueous Chang 53). the In cases or

elaboration

porphyrin

formation,

followed easily acetone and this the into

intramolecular strapped
0

Dieckmann

condensation complexes the porphyrin model iodosyl ligand models by the increased A Unlike of the

amide-linked move at
156

porphyrins only rapid

Because

sideways 20 have the itself A 5-7 the Raman the by C also system

attempts prepared was as series of

oxygenate

showed

irreversible amide-linked a

state. (Scheme In also prepared strain

Kuo

instance strap 185b. containing to

used he of units of

cytochrome alkanes the

investigate being

porphyrin-catalyzed

hydroxylation served similar

unactivated substrate, in O2 a and to and ring the and

some been in

porphyrin strapped Such displayed between bending strapped linked159,160. halves by Conden"strappedgave

transformed an

amide-linked CO

porphyrins

prepared attempt Using

methylene

strap157.

mimic and adopted of strap In is

differentiation Fe-CO Baldwin is

systems.

resonance straps) was

spectroscopy stretching et al.,

correlation Fe-C-O prepare are the is he two

(shorter strategy it the

vibrations has been observed158. different the synthetic the attached anion Acid the of porphyrins where previous ortho-positions is the ends. strap to and both opposite which the with final stretched meso-phenyl prepared step into the rings

syntheses,

initially porphyrin

porphyrin of 187 the 186.

formed

intramolecular sation ylate the to dialdehyde" unstable give he the

cyclization

position benzyl which

(Scheme gave

54).

salicylaldehyde catalyzed chain-linked This was presence was not of porphyrin

1,12-dibromododecane with after with yield.

condensation immediately 190 able in to

3,4-dimethylpyrrole-2-carboxhydrogenolysis trimethyl As of in the the orthoformate previous respective 191 was

afforded tetraacid alkyl In

bis-dipyrromethane, 23% enforce base the

189. strap the

condensed overall

"alkyl-strapped"

examples iron(II)

five-coordination six-coordinate

complex.

excess

species

formed which did not bind oxygen. Reducing the concentration of base led to an increase

172

173 of the four-coordinate was species at which -550C by underwent similar to irreversible unhindered et al.161,162), enough corners two oxidation. porphyrins, who to of were cause a of While warming attempting deformation preformed the reversible to to of room strap the were

oxygenation A a similar

observed was

temperature caused -oxo bridge formation (Scheme 55). approach with best, very in give used alkyl case, poor Wijesekera chains linking yields. porphyrin at short this very short opposite the

porphyrin. would,

Obviously

porphyrin

Instead

halves

porphyrin

assembled at each end of the strap, and only at the last step was the porphyrin 192 formed by acid-catalyzed intramolecular cyclization under high dilution conditions (Scheme 56).

Visible

and

H-NMR

spectroscopy

and

X-ray

crystallography

(Fig.

7)

all

point

to

increas-

ing distortion of the ring as the length of the strap is decreased (192, n = 11, 10, 9). A 174 chain length of nine methylene units appears to be the lower limit; attempts to prepare even more strained porphyrins with shorter straps were unsuccessful. Ligand binding to the metal complexes showed that the straps provided no steric protection.

Fig. 7. Ortep drawings of 192 (n = 9). Adapted from Ref. 162

175

6.B. Straps Containing Bulky Blocking Groups

Porphyrins oxo The bridge to logical One of strapped with In is simple alkyl chains is some the are not face bulky poor models from into for oxygen binding the increase heme heme strap, the proteins. In most cases the strap is too "floppy" and can be pushed to one side allowing \iformation. oxygen extension the addition, on to base the prevented and, group binding the strap under to to leading binding open consequently, irreversible oxidation.

incorporate of

steric encumbrance about one face. initial examples strapped porphyrin approach protein models was the cyclophane porphyrin 193 of Diekmann et al.l63). In this example steric

176

encumbrance strap, poor yield

was (5% not

provided cyclization for the used

by was as a

biphenyl delayed step heme

group until after

in the

the final

strap. step

To

ensure

tigh ly

fitting of this

porphyrin was

(Scheme an

57).

Because was

cyclization

repeated

chromatographic

purification)

porphyrin

protein

model.

Instead

anthracene

strapped

across a preformed porphyrin (194) by means of amide linkages (Scheme 58). For the

177 anthracene-heme[6,6]cyclophane ~4.5 dione of a apart. (196) second A gave axial 198 Diels-Alder the "pagoda base being 198a 195 the addition porphyrin" the two on 197 even 7,7] aromatic the possessing ring I M compound in rings an were with not I-MeIm. 198b even estimated pocket. the to to be

anthracene was

l-phenyl-triazine-2,5Binding iron(II) study

tighter

underneath and the

anthracene

observed, The were used

complexes

five-coordinate

anthracene-

heme[6,6]cyclophane

homologous[

the binding of isonitriles, CO and O2 within the pocket as models for the distal side steric effects in heme proteins164_166.

The compared effect), This but due

Fe[6,6] to flat this and to linear

cyclophane unhindered steric distal

198a

showed ( he

large

reduction cyclophane in to distal

in the

affinity ligand in

for

CO only

and a

O2 small

hemes was steric the bulky or

Fe[7,7] are face.

198b

showed the

effect side to

manifested effects heme

primarily not due While

association bound the in not and his

rate167. state, model

suggested

that limited

repulsion steric they

access bent

effects could

compounds between to postulate Baldwin benzene capped" which did not Dolphin durene did

could and that

differentiate reported his one the

isocyanide These of tilting

ligands, results CO to bound

differen iate colleagues be with the and of a "C2strap which a a may 199 to

diatomic bending strapped face absence bridge

molecules.

led in

Traylor heme a

proteins system similar in a

minor chemical significance. adapted above 160, u-oxo his prevent porphyrin (Scheme of the by synthesis 59)160. two ligands An extra such even a prepare ring not Although as more series structurally resulted or bulky of I-MeIm

porphyrin prevent and

linkages

"floppy"

six-coordination

pyridine

formation. have (201)

strap,

incorporating with

naphthalene ring as in 200, was no more successful. colleagues161,162) one face prepared (Scheme strapped of porphyrins iron using group protecting 60). Incorporation stan-

dard methods168 gave the corresponding heme complexes 202a-c. The crystal structure

of that

the

hemin from 201c 201c 201b

chloride

derived The

from

202a also in

(Fig. spectra the data plane of

8) for

showed the

considerable free base base the tighter CO, are

distortion porphyrins while moiety 5/5 been

of the in and

the
7/7-

porphyrin some derivative

7/7-base

planarity169. distortion essentially closer 201a. their of to is is and to

optical
1

indicate the
-4/4

porphyrin

exists flat. he heme

durene-5/5 suggest than the in

free that the

201b, durene capped have and

H-NMR

porphyrin with of in the the

analogs with binding Me2Im) durene

The

derivatives

durene and

porphyrins

studied The (1,2the reasons,

respect to

interaction side

imidazoles,

isocyanides, hemes

O2114170. within

constants the series

1,5-dicyclohexylimidazole differences

(DcIm) plane

1,2-dimethylimidazole similar for steric

unhindered despite

four-coordinate porphyrin

distortion;

these imidazoles do not coordinate on the capped (or distal) side of the heme. The size of

179

180

Fig. 8. A SNOOPI diagram (E. K. Davies, plotting rou ine, 1984, Chemical Crystallography Laboratory, 9 Parks Road. Oxford. England) of the hemin chloride of 202a (50% probability contours for all atoms; hydrogen atoms have been omitted for clarity; the dashed bonds are used to distinguish between the "strap" and the porphyrin skeleton)

202

the (TMIC)

distal and

cavity restrictive of

was distal

examined (t-BuNC), environment isocyanide.

using which of The

the the

bulky in durene-4/4

isocyanides, their spatial system,

tosylmethylisocyanide requirements. inhibited obtained The the from

t-butylisocyanide either

differ

extremely coordination

however, complex

Fe"(durene-7/7)(DcIm)

202c exhibits a reduced overall affinity for CO relative to simple flat, open hemes; this is

181 manifested steric effect in as a a from depressed result of association the rate for The CO, and was and CO strain a interpreted170
-4/4

as

distal from

durene-cap. dissociation of the

durene-5/5 for steric

systems the by

derived

202a and 202b also show reduced CO affinities compared to open hemes, but this results predominantly Fe(P)(DcIm)CO Me2Im) skeletal 202b relative heme values) distal within bind B to (or O2 increased because to rates proximal from induced six-coordinate the of porphyporphyrin relative of to CO (M their of complexes O2

rin plane distortion. The five-coordinate hemes 202a B - 202c B (B = DcIm or 1,2reversibly A less similar extents, arises all implying from negligible 202a steric effect distortion. 10-fold reduced distorted his B is affinity for CO hemes) B that the in a base distorted by the system. show with Fe-O2 B complex the

other 202a to

proximal

discrimination kco/k2 functions electronic the strap cavity significant was and

within

severely 202c hemes stabilizing (as face of CO, O2 the O2 the

Significantly, higher amide of polar concept and was give showed to the displayed binding straps heme

five-coordinate ratios in

complexes relative the distal

considerably the

encumbered This pocket strategy one

incorporate

environments.

entirely

consistent

interactions affinity a

binding

moiety 58) to 9) bind the

increasing used no Fe" no constant of 204 257 to free

the heme toward O2, relative to CO114'170. The phane. the greatly same The synthetic shown of free and Scheme porphyrin (Fig. bulky cyclobetween 203 with steric adamantane strap group crystal the and across l,3-adamantane[6,6] complex

structure171 porphyrin; CO the no

isocyanides For the CO

reduced

rates.

However and

adamantane

strap

differentiation In Chap. et the strap

between to a

binding. of

controlled 259 by (see Traylor formashorter 204

by the association rate, dissociation not being increased by the steric effects of the strap. contrast 6.C.), ligand strapped evidence and bases behaviour of to either iron(II) strain pyridine or singly pyridine-[5,5] cyclophane prepared

al.172,

showed of

internal

external is

iron-pyridine

complex the

tion. Indeed even the binding of CO to 204 failed to induce pyridine ligation even though binding in this CO case porphyrins to prevent synergistic. binding Obviously and induces sufficient internal compound

behaves more like the anthracene and adamantane cyclophanes 198 and 203. The

Fig. 9. Perspective view of a l,3-adamantane[6,6] cyclophane porphyrin. Adapted from Ref. 171

182

pyridine between

heme in CO

204 and

displays O2

severe than

steric rates. other

hindrance Furthermore models, the

to the

both 204

O2

and a binding

CO

binding, being

which

is

manifested

lower

association binding have

shows

greater ratio

differentiation possibly in

lower of

due to enhanced binding of O2 in the tight polar pocket114. Dolphin and Morgan173 prepared series strapped porphyrins illustrated Fig. 10 and Scheme 61. As a consequence of postponing porphyrin ring formation (a

183

Fig. 10. Ortep drawings of a strapped porphyrin containing a thioether linkage. Morgan, B., Dolphin, D., Einstein, F. W. B., Jones, T., manuscript in preparation specific example is given in Scheme 61) till the later stages on the synthesis, (i) a range of strap (ii) ester strap lengths linkages have are available, may (iii) some be of which stability 10), 61) as may is lead obtained 205 and potential to any distortion polar due to for of the 206 the due porphyrin, to amide in and or the strap. catalase hydrocarbon straps and employed, (Fig. precluding phenol effects

increased (Scheme

hydrocarbon groups174 c,

Compounds

including been

thioethers

quinone

prepared

models

cytochrome

and photosynthetic charge separation, respectively.

184

6. C Straps Containing Interactive Groups

The incorporation of potential ligands into the porphyrin strap has three advantages, (i) A stoichiometric amount of ligand is built into the system, ensuring five-coordination without the addition of external ligand. In the case of nitrogen bases, mixtures of six- and four-coordinate complexes are avoided. (H) For ligands which bind poorly to iron(II) (e.g. thiolate), coordination would be favoured by constraining the ligand into a position suitable for binding to the metal, (iii) Because the strap is fixed to the porphyrin and the ligand in two positions, complications due to ligand replacement or dissociation will be minimized. The strapped-porphyrin approach is also useful for orientating other interactive groups (e.g., metal binding sites, electron donor/acceptor groups) into specific geometries with respect to the porphyrin.

185

Battersby substituted 38% yield is corresponding syntheses (Scheme

et pyridine

al.

have ligands175. diol 62). in suitably

prepared Reac ion gave 11176). 207 The

a of the A

series the

of

strapped pyridine a P450 was

porphyrins chloride straps was under

bearing 180 in 208a-c

variously with up of the to these similarly with

porphyrin of

bis-acid crystalline model reacted

pyridine (Scheme shown A

ester-linked structure cytochrome

molecular

side-product prepared high

Fig.

63)177.

functionalized

diol

211

dilution

the bis-acid chloride of mesoporphyrin II (180) to give the strapped porphyrin 212 in 25%

186 yield. group the iron(II) whose monoxy 450 nm. Several binding formed bind ether face a two The with S-acetyl species. visible The protected-sulfur potassium group On was derivative cleaved to spectrum spectrum spectrum strapped in a ion of 213 with CO a a was iron dimsyl obtained sodium the hyper CO major Soret by to iron(II) band also displacement reduction to produce species with an of the the 214 of the are 217 IIA the iron(II) was the tosyloxy state, formed carbonband at

thioacetate. exposure

After

insertion

and

five-coordinate

six-coordinate

absorption P450
13

reproduced split the

13

characteristics supported which

cytochrome

intense

C-NMR

complex been

RSFeII-CO capable of of

formulation. binucleating metal ions porphyrins proximity. porphyrin Apart over have The e her ring) from one prepared, the group the bind Oxygen close (in the 64). control a "crowned" 216 to and its face a of metal porphyrin IA or Chang178, 215, may (in the the the crown iron(II) the

by the addition of transition also exerts bulky metal ring) some Iigands to

bis-amino crown

bis-acid chloride capability For the bind on then

cation

diaza-18-crown-6 complexes, of the

(Scheme steric (e.g., give

binding only may

porphyrin.

1-triphenylmethylimidazole) five-coordinate species.

unhindered under

porphyrin

crown to give a reasonably stable oxygen species (t1/2 > 1 hr at 250C in DMA).

Recently, he and rate (Scheme cations

another of The

crown-strapped 225b (see corresponding Bimetallic indicated crown fluorescence

porphyrin Scheme

219 67) were

similar with is a

to the

217

has host for at

been crown for with the

prepared ether both the

by 218

condensation 65)179. e.g. of Cu", cationic salts The

bis-amino and, salt

metalloporphyrin quenching of was the

potential

anionic guest perchlometal

species. FeIII, diamines of have 66). acid provided compound

complexes attachment and the of of to

prepared perchlorate has also

paramagnetic porphyrin out wi h (221) 10% and by

observed.

Studies

site and complexation of the ammonium species at the crown ether. combination who acetic 222 This (Scheme e her porphyrin been carried 220 and Bogatskii by pyrrole with group I, yield two in the II et al.180, prepared Condensation or the is reac ion tetra-crown reported wo-tetra(benzo-18-crown-6)porphyrin 4'-formylbenzo-18-crown-6 porphyrin 223 in 4% tetra(3,4-dihydroxyphenyl)porphyrin form complexes with transition 223

routes refluxing dichloride tively. metals.

ether

respec-

The ton et

combination al.1B1 at 55 The

0

of

crown ether

ether 224

and with

porphyrin 226 the

has was

recently prepared

been by

extended

by

Hamilof b the in

macrotetracyclic under high

cryptand dilution

condensa ion porphyrin 225a,

biphenyl-linked pyridine

bis-crown C

di-p-nitrophenyl (45-54%

ester after

conditions

chromatography).

Reduc-

tion to the tetra-amine 227 was effected by treating the zinc complex with diborane

188

followed selective within

by

demetallation binding:
+

(Scheme transition

67). metal (n =

This

multisite are within

complexing bound the the by by

species the cavity. upfield

is

capable and of That

of alkyl the

substrate salts, cavity

cations 8-10),

porphyrin

diammonium the

H3N(CH2)nNH3+ indeed

central large

binding

does

occur

was

evidenced

shifts

methylene protons due to the shielding effects of the porphyrin and biphenyl rings.

189

A mimic The cine the

copper the 228 in

binding

site

has was

been a of

covalently of the

attached derivative for a

to

porphyrin of obtainable than to 231 in

in

an from

attempt

to

EPR high of

spectral strap yield. the to

characteristics Because the of

iron-copper

site

cytochrome copper

oxidaseI82 phthalylglysite,

copper-binding strap was (230) and and a by

bis-thiazole need the the a sulfide ions of

229,

non-square-planar ring rather with

binding XII

attached under into

one side dilution 68). to The et

porphyrin 229 strapped could coupling a

opposite 72% a to

corners. bis-acid after the spin was a

Condensation chloride porphyrin iron(III) chromatography

diaminothiazole gave give al.183, Metal

mesoporphyrin

high the

porphyrin complex

yield into high centers

(Scheme copper(II) EPR.

be metal

differentially the

introduced containing two metal approach

strap ion.

dinuclear

extent

between

investigated

Gunter

used

somewhat

different

prepare

similar Fe/Cu strapped porphyrin (Scheme 69). Condensation of the tetramethyldipyr-

190

romethane ers 235. were

232

wi h

o-nitrobenzaldehyde After by reduction

(53), to

followed the

by

oxidation 233

afforded was the

the the

5,15-meso(orthoatropisomers condensed gave species and of yield dioxide. the with of porphyrin

nitrophenylporphyrin. separated of model iron

amino and yielded of

derivative

chromatography. chloride) copper and

The (234), the and

cc,a-isomer introduction

finally ligands

2.6-pyridylbis(4'thia-5'-pentanoyl Insertion As esh185,186 tersby bis-acid on a and

strapped

bridging

the type 236, whose magne ic properties were investigated184. for photosynthetic a give electron-transfer porphyrin. 237 porphyrins quinones d and Using 238 239a, that in b the were with systems, the 7 reacted boron Sanders wi h and with 15% lead trichloride quinone GanBatII the to have group, chloride strap on prepared (180) to were that quinone-capped deriva ives strapped to the the c, the 70). approach

1.4-dialkoxybenzene length which (Scheme

mesoporphyrin afforded binds

depending 'H-NMR perpen-

Deprotection 239

hydroquinones studies the the metal

oxidized complexes theretore

magnesium and

suggest

carbonyl are

ion

quinone

porphyrin

chromophores

dicular187.

Since oxygen sponding auenchine parallel nesium

zinc ligands, zinc is approach

is

exclusively

five-coordinate binding free of especially base is the

in the

porphyrins chromophores with and added zinc is are the with but

and is 239e,f much

has

low in

affinity the where

for correclose, mag-

intramolecular complexes in the 239c.d of the of the

lessened

239e,f

ligands

present. complexes reduced for The

Fluorescence the

observed of

239a,b

chromophores where

possible,

complexes binding

chromophores in diols 239c,d 240

perpendicular"*'. quenching 180 gave

quenching is similar strapped

is more efficient for the longer chain 239b. f than for the shorter chain 239a. e; because of intramolecular High chromophores the bipyridyl efficiency the bipyridyl for both chain lengths. dilution coupling porphyrins 241 (Scheme 71) in 40-50% yield189 191 Treatment with iodomethane fur-

191

192

nished donor potential reduced was

the

methylviologen and

strapped an

porphyrins acceptor of

242.

The

close

proximity dication) of 241 to by 243. give the into

of and the

an 242 two

electron this a were It radical of the at

(porphyrin) ~200 fold that et II

electron Indeed to

(methylviologen emissions methylviologen electron and

makes

photosyn hetic

model.

fluorescence an excited a

relative efficient have with 72).

mixtures of

unstrapped

porphyrin.

assumed Hamilton

trapping also

occurred complex diol two

cations of the connected chromophores. al.192, diacid 244 (Scheme prepared 180 close with binuclear the by of condensation Reaction the of mesoporphyrin strapped resulted in chloride The bipyridyl metal the

porphyrin 245

Ru(byp)2Cl2

followed proximity

insertion metal

porphyrin

4 is reflected in both the luminescence and electrochemical properties of the complex.

centers,

estimated

6.D. Doubly-Strapped Porphyrins

We have oxo face. bridge Steric of already seen formation Amundsen and his and to if encumbrance that sterically encumbered porphyrins any on and four-coordinate both faces of Vaska148 and have on species the in porphyrin, may may still binds in the as be susceptible to on he "bis-pocket" a solution oxygen this open oxidaprepare of salicylformed

porphyrin

systems

Suslick149, used a

prevent of In the TPP a and

bimolecular to of then

tion pathway. Momenteau TPP derivatives was 246a-e Baldwin's aldehyde derivatives colleagues two straps with a "strapped" combination ring193. approaches strategy sodium ring salt was having reacted give each porphyrin of reminiscent

"capped"

porphyrin variety

syntheses159-160), dibromoalkyl 247. The

p-(dibromoalkyl)benzene

chain-linked

dialdehydes

by condensing the dialdehydes with pyrrole in refluxing propionic acid (Scheme 73).

193 After in low minant formation (Scheme removal overall isomer. of 74). of yield. To the polymeric The bridges (10% Alkyla ion by followed increase materials, the was yield three of the until isomers cis-linked more after (249) dibromo led to were product interesting the was obtained 248c was cross by chromatography the predoisomers, and dilution porphyrin

unwanted

adjacent delayed and the

often

trans-linked from under

porphyrin-forming obtained to isolation 246 of provide the

condensation pyrrole high hree tetra(o-hydroxy-

Tetra(o-methoxyphenyl)porphyrin yield) with (250).

o-methoxybenzaldehyde phenyl)porphyrin in DMF at 100C,

demethylated the

derivatives

chromatography

isomers 248. In this case the major product of each reaction was atropisomers since the conditions of the condensation would lead to equilibra ion.

he desired cross trans-

linked isomer 248a. The starting porphyrin 250 was used as a mixture of the four possible

The tion and of is

degree the iron easily

of

steric

encumbrance The In contrast do

is the

illustrated cis-linked other not

by

the

rates 248c where

of has both of at t 7-54

metallation one faces face

and

oxida-

various

isomers.

adjacent While inhibit

isomer

unhindered hindered, bases to 25 or For the oxida0

metallated. insertion the

isomers,

are

undergo diatomic the tion under The metallation try. paralleling A hematin of O2

reluctantly. chains cross is isomers

preventing isomer

ligation he to

nitrogenous room for in oxidation seconds toluene is

molecules, derivative the (1 less atm),

irreversible minutes u-oxo the

oxidation 248a

temperature. for at 11-25 only

four-coordinate

iron(II) FeIII(P)OH hindered t1/2

trans-linked 1.5-10.5 to the of

compared complex.

Similarly, iron(II)

for

oxidation picket-fence small

six-coordinate show in the the their iron free

complex effects and have

min

for the cross trans-linked isomer compared to 1.5-12 min for the other two isomers194. basket-handle and the binding on earlier studies and of porphyrins but of on been the dramatic redox not during chemismade195' and al. . hat zinc The with do molecules studies has in the coordination been magnesium Zhilina was et

Detailed

the

electrochemistry

complex base, by (142) of The

electrochemical porphyrin

complexes of 192 and 201196. similar doubly-strapped of room at reported a,b,a,b triglycolic not cause atropisomer dichloride significant meso-tetra(o-aminophenyl)porphyrin temperature of presence atropisomer. acylated

pyridine,

conditions

isomerization

doubly-strapped

porphyrin

251 was obtained in 32% yield after chromatography (Scheme 75).

In a units. yielded desired

contrast Thus, a cross

to

the

sequential to prepare of the

introduction a and bis-aldehyde

of

bridging with

straps, pyrrole was and

Weiser in

and

Staabl98 propionic

used acid The its

one-step

synthesis mixture of

porphyrin polymers, obtained

sandwiched 252 in and three ~0.1%,

between

two refluxing

parallel

quinone

condensation trans-linked symmetric

1

oligomers H-NMR

doubly-strapped easily oxidation

porphyrins. identified then by

porphyrin,

characteristic

spectrum.

Deme hylation

yielded

the desired bis-quinone porphyrin 253 (Scheme 76).

A globin, of the

further

refinement models of system a

to

he

production different base steric

of

heme one

protein As

models for by

was

the the

synthesis or proximal strap

of face

doubly-strapped natural

containing nitrogen the while

straps.

models would

hemoglobin second

myowould

incorporation

into

strap

simulate the

encumbrance

provided

mimic the distal, oxygen-binding face.

Momenteau's compounds tion lent on of of in

route which an

to

doubly-strapped base gave or by to was (250) a

porphyrins incorporated (mixture of (254) tic (5% of two

was into one four

easily of

adapted the wi h were desired

to one

produce Condensaequivadepending This transsimilar in of this 78). both

axial

straps199' porphyrins,

tetra(o-hydroxyphenyl)porphyrin 1.12-dibromododecane adjacent reacted 257 was were insertion (255), with was

isomers) groups the

mixture

singly-linked and yield) amide and

1

whether isomer 259 the

opposite preparative from the

meso-phenyl 256 overall by

linked. cross A

mixture linked case porphyrin Following

3,5-bis(3-bromopropyl)pyridine

isolated tied and

(Scheme linkages

77). (142); spectra

prepared

a,b.a,(3-tetra(o-aminophenyl)porphyrin porphyrin visible skeleton absorption H-NMR

straps iron

(Scheme

reduction,

compounds were consistent with a five-coordinate high spin (S = 2) iron(II) complex.

The by laser of

rate constants for the flash ca. of photolysis. 10 in he The O2

association O2 affinity

and of

dissociation of O2 and CO were determined the "amide" koffO2 linked 4 vs to system 0.5 the s_l). was This higher than in N-H

that of the "ether" linked compound p 18.6 vs 2 torr) as a result of a difference of a factor stability dissociation rates (10~4 was increase of the the "amide" oxygenated species attributed presence

group and the possibility of hydrogen-bonding with the terminal oxygen atom. The low

temperature quivalence of

(-27C)

H-NMR

spectrum

supported

this

hypothesis,

the

observed

ine-

he pyrrole protons as well as

he shifts of the amide protons suggesting a

preferred orientation of the oxygen molecule towards the amide N-H groups200. To better model the hemoglobin and myoglobin active sites a doubly strapped heme 260 was prepared incorporating a pendant imidazole (Scheme 79)201. 260 was capable of binding oxygen to give a rela ively stable oxygenated species (lifetime was about one day in dry toluene under 1 atm O2). The kinetics of O2 and CO binding have been determined and initial comparisons with the comparable "pendant pyridine" porphyrins show: (i) (ii) O2 and CO combina ion rates are practically constant in the three pendant base porphyrins, and a reduction in konO2 in the imidazole porphyrin due to a combination of hydrogen bonding with the amide N-H and the greater basicity of imidazole over pyridine. Comparison of the pendant imidazole model with myoglobin or isolated hemoglobin chains shows that the model reacts 10 times faster with O2 and that the dissociation rate is approximately 100 times faster than in the natural systems. With the availability of the differentially protected coproporphyrin I 261, Battersby and Hamilton adapted heir syntheses to the production of doubly-strapped porphyrins

(Scheme ridine esters 263 with to difficult and so

80)202. the the acid the

Reaction chloride metal

of

the

bis-acid porphyrin was after be a

chloride 262 by

261

with

3,5-bis(3-hydroxypropyl)pyof the found strap. of min the of to the at benzyl diol be to with the was basis 15 was into anthracene

yielded give

pyridine-strapped formation inserted the to doubly-bridged was furnished judged In DMF

(33%). Iron of = of

Hydrogenolysis insertion the on 2) the

followed 264 the high with

condensation

porphyrin iron(II)

(27%).

introduc ion species spin a t1/2 stable was (S

pyridine

Reduction visible to (t1/2 Such This room

aqueous gave in

dithionite was an

which

absorption oxygen temperature and was

spectrum

five-coordinate. species CO by

Exposure formed O2.

oxygenated

compound O2 six of

approximately by passing

CH2Cl2of to the be the

more species times

oxygenated accomplished significant CO-porphyrin imidazole (57%).

approximately 2 regeneration cycles in The reported203'. the esters yield cycles and contrast further As O2-CO

h at 20C). The could repeated

could be

displaced without

solution,

oxygenated resistance of give

passage

irreversible complexes ligand 261 was has was removal reacted oxygen being was

oxidation.

unhindered an

displacement recently with benzyl the in N22% four before ca. rigid before gave he

of CO by O2. refinement before, diol 263 with diol The the to incorporating the porphyrin the was The been of the with differen ially chloride, The complex (by occurred. protected coproporphyrin After 267 chloride of the still 268 268a reacted

anthracene

265 bis-acid capable

treatment imidazole 81).

oxalyl 266. iron(II)

substituted of

doubly-bridged reducing t1/2

porphyrin the for was

obtained possible species floppy,

(Scheme

reversible

binding, was more as

oxygenation-deoxygenation irreversible that oxidation the a he

pressure)

significant

oxygenated somewhat were or

24 h at room temperature in DMF solution. Recognizing straps (Scheme imidazole pendant-imidazole 1,5-disubstituted bis-acid chloride strap imidazole of the containing 81)203). 268b with prepared porphyrin

Coupling

1,5-bis(4-hydroxybutyl)

l,5-bis(3-hydroxypropyl)-

anthracene-strapped

doubly-bridged systems 269a, b in 23% and 6% yield. Distortion of the porphyrin ring

198

from the ture. dation

planarity iron(II) Ten was

to

accommodate could and

the

shorter bind cycles 20%

strap oxygen could

was in be

believed DMF

responsible at

for

the

low

yield of 269b and also for the lesser stability of the oxygenated iron(II) species. For 269a, complex reversibly only solution occurred ambient after 2 temperaoxiin days oxygenation-deoxygenation significant, performed before irreversible

irreversible

oxida ion

solution. Acknowledgements. This work was supported by the United States National Institute of Health (AM 17989) and the Canadian Natural Sciences and Engineering Research Council.

7. List of Abbreviations
acac AQ bipy 1-n-Bulm 4-t-BuIm t-BuNC BO CO Cys cyt DCIM DDO DMA acetylacetonate Anthraquinone bipyridyl 1-n-Butylimidazole 4-t-Butylimidazole t-Butvlisocyanide Benzoquinone Carbon monoxide Cysteine cytochrome 1,5-Dicyclohexylimidazolc 2,3-Dichloro-5,6-dicyano-l,4benzoquinone N1N-DimethyIacetamide DMF DMSO DNA ee Et3N EXAFS N1N-DimethyIformamide Dimethylsulfoxide Deoxyribonucleic acid enantiomeric excess Triethylamine Extended X-Ray Absorption Fine Structure H2(OEP) Octaethylporphyrin general porphyrin H2(P) H2(TAP) Tetra(p-methoxyphenyl)porphyrin H2(T(OH)PP) Tetra(o-hydroxyphcnyl)porphyrin H2(TPP) Tetraphenylporphyrin

H2(TTP) His Hm Im MCD I-MeIm l,2-Me2Im MeOH Met NQ

Tetra(p-tolyl)porphyrin Histidine Heme Imidazole Magnetic Circular Dichroism I-Methylimidazole 1,2-Dimethylimidazole Methanol Methionine Naphthoquinone

phth piv THF THT TMIC Tos Tr l-trityllm Tyr

phthaloyl pivalamido Tetrahydrofuran Tetrahydrothiophene Tosylmethylisocyanide Tosylate Trityl I-Tritylimidazole Tyrosine

8. References
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