8084
J . Org. Chem. 1998, 63, 8084-8085
Sch em e 1
Im id a zole Acid Ch lor id es: P r ep a r a tion a n d
Ap p lica tion in th e Syn th eses of Biom im etic
Hem e Mod els
J ames P. Collman,* Martin Bro¨ring, Lei Fu,
Miroslav Rapta, and Reinhold Schwenninger
Sch em e 2
Department of Chemistry, Stanford University, Stanford,
California 94305-5080
Received September 9, 1998
The design of biomimetic metalloporphyrins has long been
a successful strategy to study the structural requirements
and mechanistic details of the multiple functions of heme
proteins in nature. Among the amino acid residues that
heme proteins employ to modulate the heme environments,
the imidazole moiety of histidine is the most common one.
Three important tasks, axial ligation of the heme iron,
coordination of nearby metal centers, and stabilization of
heme dioxygen complexes, are fulfilled in nature by this
heterocycle.1,2 Numerous attempts to mimic these functions
by metalloporphyrins with covalently attached imidazole
pickets have been reported.3-5 However, none of these
approaches can be regarded as a general method. The
selective functionalization of porphyrins with customized
imidazoles remains a synthetic challenge.
In principle, the most straightforward way to prepare
porphyrins with pendant imidazoles would be the reaction
of o-aminophenylporphyrins with imidazole acid chlorides.
These, however, have been used only in a limited number
of cases, and their synthesis is generally achieved in situ in
order to avoid the handling of these particularly sensitive
compounds.
require special design in order to prevent them from
coordinating to the central metal ion of the porphyrin for
most applications. This can be accomplished by using
shorter linking units (<C3) as demonstrated in 15 and 17
(Scheme 3) or by introducing a steric bulk, such as diphe-
nylimidazole derivative 19, if a longer imidazole-to-porphy-
rin distance is desired. The preparation of the acid chlorides
15, 17, and 19 as stable, solid materials from the respective
acid hydrochlorides is best performed using the same condi-
tions as for 3, 9a , and 9b.
Our initial attempts to attach the new imidazole acid
chlorides to o-aminophenylporphyrins under standard condi-
tions (excess acid chloride, solvent, non nucleophilic base)
failed to produce the desired products. Most likely, this
failure results from deprotonation of the imidazolium salts,
followed by immediate attack of the acid chloride, producing
oligomeric acyl imidazolium species. A control experiment
with 1-acetyl-3-methylimidazolium chloride8 showed that
this acylating agent is incapable of reacting with the
porphyrin at room temperature, probably as a result of steric
hindrance. In acetic acid, however, the nucleophilic imida-
zole nitrogen remains protonated and thus sufficiently
protected, allowing the desired transformation to occur. As
a scavenger for the HCl build-up in the course of the
reaction, sodium acetate was found to be the base of choice,
and its slow addition to the reaction mixture drives the
acylation to completion. N-Acetylamidophenylporphyrins
are formed as the only byproducts in ca. 10% yield.
Herein we report a versatile solution to this problem,
based on the preparation of stable imidazole acid chlorides
and their high yield attachement to o-aminophenylporphy-
rins in an acidic medium.
For the design of imidazole pickets which must fulfill
different purposes, the nature of the linker is of great
importance. A benzylic linker, known to be of an appropriate
length and geometry to fasten a proximal axial imidazole
to an o-aminophenylporphyrin,4 was chosen for our synthetic
scheme. The formation of the acid chloride 3 from the acid
2 using oxalyl chloride in acetonitrile constitutes the key
step in the synthesis as shown in Scheme 1. This particular
route allows a simple workup, resulting in 3 as a stable
solid. Scheme 2 outlines the application of this approach
to the 5-substituted imidazoles 7a and 7b, giving 9a and
9b in excellent yields. The intermediates 7a and 7b can
be prepared in a regiospecific manner using Horvath’s
protection strategy.6,7 The aromatic substituents were
chosen to meet the need for less polar and more soluble
final compounds. They also offer a convenient handle for
a spectroscopic probe, i.e., CF3 in 9b for 19F NMR spectros-
copy.
Scheme 3 illustrates the application of this new method
to the syntheses of the novel cytochrome c oxidase model
ligands 16, 18, and 20, using the recently developed â-
tritylated porphyrin 10 as the starting point.9 The problem
encountered in the acid-lability of the trityl protective group
can be circumvented by the introduction of the well-known
trifluoroacetamido protective group into the porphyrin struc-
ture and its selective removal with methanolic ammonia at
a later stage. As shown in Scheme 4, this new acylation
approach is also well-suited to append imidazole axial
ligands on superstructured porphyrins, such as 21 and 23,
in good yield.
In contrast to the proximal face imidazole axial ligands,
the pendant imidazoles on the distal face of a porphyrin
(1) Holm, R. H.; Kennepohl, P.; Soloman, E. I. Chem. Rev. 1996, 96,
2239-2314.
(2) Ferguson-Miller, S.; Babcock, G. T. Chem. Rev. 1996, 96, 2889-2907.
(3) Collman, J . P.; Brauman, J . I.; Doxsee, K. M.; Halbert, T. R.;
Bunnenberg, E.; Linder, R. E.; La Mar, G. N.; Del Gaudio, J .; Lang, G.;
Spartalian, K. J . Am. Chem. Soc. 1980, 102, 4182-4192.
(4) Young, R.; Chang, C. K. J . Am. Chem. Soc. 1985, 107, 898.
(5) Baeg, J . O.; Holm, R. H. Chem. Commun. 1998, 571-572.
(6) Horvath, A. Synthesis 1994, 102.
(8) Wolfenden, R.; J encks, W. P. J . Am. Chem. Soc. 1961, 83, 4390.
(9) Collman, J . P.; Bro¨ring, M.; Fu, L.; Rapta, M.; Schwenninger, R.;
Straumanis, A. J . Org. Chem. 1998, 63, 8082.
(7) Horvath, A. Synthesis 1995, 1183.
10.1021/jo981835j CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998
Collman
