Expansion by contraction: Diversifying the photochemical reactivity scope of diazo-oxochlorins toward development of in situ alkylating agents

Article abstract of DOI:10.1021/ja800094e

Irradiation of 2-diazo-3-oxochlorins (200 W, λ ≥ 345 rim, 10°C) in the presence of nucleophilic and biomimetic substrates 1-butanol, tosylhydrazine, or tetrahydrofurfuryl alcohol generates Wolff-rearranged, pyrrole ring-contracted azeteoporphyrinoids in 11-34% yield, with the corresponding hydroxyporphyrins in up to 55% yield. For metalated diazo-oxochlorins, these products compete with intramolecular exocyclic ring formation by meso-phenyl ring addition, which occurs in up to 76% yield in the absence of substrate. The dependence of product distribution on substrate is established by photolysis in neat dichlorometane. Under these conditions, formation of the Wolff-rearranged product is inhibited and the phenyl addition product dominates (76%) due to the absence of a good nucleophile. A conceptually analogous dependence is also observed for the free-base derivative, with the exocyclic ring-containing dimerization product isolated in 42% yield. The third reaction pathway, formation of the hydroxyporphyrin, is enhanced by the presence of non-nucleophilic, oxidizable substrates such as 1,4-cyclohexadiene (M = Cu; 55%); however, in the presence of the bulky and oxidatively more stable tert-butyl alcohol, intramolecular exocyclic ring-quenching is observed in 51% yield with no detection of the hydroxyporphyrin. X-ray structure characterization of the azeteoporphyrinoids reveals a planar macrocycle, illustrating the strong influence of periphery contraction. Specifically, the copper-containing azeteoporphyrinoids show remarkably short Cu-N_azete distances of 1.88-1.90 A. All porphyrinoid photoproducts possess intense absorption bands throughout the visible spectral region, indicating that ring-contracted substrate adducts, as well as phenyl ring addition products, maintain porphyrinoid aromaticity. Overall, the ability of these chromophores to photochemically react under substrate control may make unimolecular porphyrinoid photoreagents such as these useful for applications in photobiology or O₂-independent photodynamic therapy.

Full text of DOI:10.1021/ja800094e

Published on Web 10/31/2008
Expansion by Contraction: Diversifying the Photochemical
Reactivity Scope of Diazo-oxochlorins toward Development of
in Situ Alkylating Agents
Tillmann Ko¨pke, Maren Pink, and Jeffrey M. Zaleski*
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received January 5, 2008; E-mail: zaleski@indiana.edu
Abstract: Irradiation of 2-diazo-3-oxochlorins (200 W, λ g 345 nm, 10 °C) in the presence of nucleophilic
and biomimetic substrates 1-butanol, tosylhydrazine, or tetrahydrofurfuryl alcohol generates Wolff-
rearranged, pyrrole ring-contracted azeteoporphyrinoids in 11-34% yield, with the corresponding hydroxy-
porphyrins in up to 55% yield. For metalated diazo-oxochlorins, these products compete with intramolecular
exocyclic ring formation by meso-phenyl ring addition, which occurs in up to 76% yield in the absence of
substrate. The dependence of product distribution on substrate is established by photolysis in neat
dichlorometane. Under these conditions, formation of the Wolff-rearranged product is inhibited and the
phenyl addition product dominates (76%) due to the absence of a good nucleophile. A conceptually
analogous dependence is also observed for the free-base derivative, with the exocyclic ring-containing
dimerization product isolated in 42% yield. The third reaction pathway, formation of the hydroxyporphyrin,
is enhanced by the presence of non-nucleophilic, oxidizable substrates such as 1,4-cyclohexadiene (M )
Cu; 55%); however, in the presence of the bulky and oxidatively more stable tert-butyl alcohol, intramolecular
exocyclic ring-quenching is observed in 51% yield with no detection of the hydroxyporphyrin. X-ray structure
characterization of the azeteoporphyrinoids reveals a planar macrocycle, illustrating the strong influence
of periphery contraction. Specifically, the copper-containing azeteoporphyrinoids show remarkably short
Cu-Nazete distances of 1.88-1.90 Å. All porphyrinoid photoproducts possess intense absorption bands
throughout the visible spectral region, indicating that ring-contracted substrate adducts, as well as phenyl
ring addition products, maintain porphyrinoid aromaticity. Overall, the ability of these chromophores to
photochemically react under substrate control may make unimolecular porphyrinoid photoreagents such
as these useful for applications in photobiology or O2-independent photodynamic therapy.
Introduction
DNA alkylation is one of the prominent modes of action of
potent natural products (e.g., mitomycins,1-6 duocarmycins,7,8
acylfulvenes9-11) involved in drug development. Although
structurally distinct, the kinamycin family12,13 of the diazoben-
zo[b]fluorene antibiotics are functionally related due to their
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ability to alkylate biological substrates. The kinamycins and
glycosylated, dimeric lomaiviticin A and B constructs (Figure
1) are proposed to function by loss of N2 from a terminal diazo
unit. They are effective against Gram-positive bacteria, and
kinamycins A and C have been shown to inhibit growth of both
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15864 J. AM. CHEM. SOC. 2008, 130, 15864–15871
10.1021/ja800094e CCC: $40.75
2008 American Chemical Society

Diversifying Photochemical Reactivity of Diazo-oxochlorins
A R T I C L E S
Chinese hamster ovary and K562 cells,13 while in the broader
NCI 60-cell screen, kinamycin C reveals high nanomolar IC50
values similar to the potent antitumor agent mitomycin C. The
homodimer lomaiviticin A also exhibits activity against Gram-
positive bacteria and a variety of tumor cell lines, with IC50
values ranging from 0.7 to 6.0 nM.14 Despite these studies, and
the luxury of synthetic access to the kinamycin natural prod-
ucts,15 the precise mechanism of biological activity is still not
fully understood. However, it is generally accepted that the
reaction pathway responsible for cell growth inhibition involves
formation of a primary radical species via N2 loss.13,14 Along
with the enediyne natural products,16 the diazoparaquinone
antibiotics are a rare example of intramolecular diradical
generation via mild activation.
mediated PDT for hypoxic environments. Carbenes formed by
N2 loss can undergo alkylation reactions via the singlet
intermediates, or H-atom abstraction from external substrates
usually via the triplet state.42-44 Additionally, if the loss of
dinitrogen occurs from a R-diazo ketone framework, the
electron-deficient carbene can facilitate intramolecular Wolff
rearrangement,45,46 which results in a transient ketene that adds
nucleophiles.47,48 In this sense, biology provides a variety of
potential nucleophiles such as the sugar backbone of DNA and
other basic substrates.
With these motivations, we are pursuing the development and
diradical reactivity of diazo-oxochlorin chromophores.49-53 Due
to their intense absorption bands throughout the visible spectral
region,54,55 porphyrins and chlorins are routinely employed as
1
effective photosensitizers for O2 formation in PDT. Conse-
The uniqueness of N2 release as an entropically driven trigger
for reactivity leads to several potential biological applications
for diazo analogues that include nuclease activity,17-23 photo-
affinity labeling,24-38 and photodynamic therapy (PDT).39,40 The
quently, improved synthetic strategies have led to the develop-
ment of porphyrinoids with modulated optical56-59 and elec-
tronic properties.53,60-62 By combining the electronic features
of such chromophores with the alklyation, H-atom abstraction,
or Wolff reactivity of the diazo-moiety, novel porphyrin
photoreagents may be accessible.
41
formation of toxic radicals without the need for O2 suggests
that such compounds could be an alternative to traditional, 1O2-
Herein we describe the photoreactivity of diazo-oxochlorins
in the presence of nucleophilic substrates. Broadband photolysis
generates an initial carbene intermediate that differentiates
reactivity on the basis of the availability of nucleophile. In the
presence of substrates, the unique, ring-contracted azeteo-
porphyrin-substrate adducts are obtained, while in their ab-
sence, exocyclic ring formation and H-atom abstraction domi-
nate the product distribution. Photochemically initiated and
controlled addition chemistry of this type may ultimately find
utility in photobiological labeling and alkylation applications.
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A R T I C L E S
Ko¨pke et al.
Scheme 1. Summary of Reaction Products Generated by Broadband Photolysis of 2-Diazo-3-oxo-5,10,15,20-tetraphenylchlorins
Table 1. Experimental Conditions and Isolated Yields for
photochemical product isolated. Interestingly, in the absence
of nucleophile (experiments 4 and 8, Table 1), only the
unimolecular quenching product M4 is obtained in high yield
(66-76%). In contrast, photolysis of H1 in the presence of
1-butanol as a nucleophilic substrate generates adduct H2a in
34% yield, along with 10% of a new species, the dimeric
radical-radical coupling product of two exocyclic ring-contain-
ing monomers (H5). For photoreactions devoid of nucleophile,
this dimeric species dominates and is obtained in as high as
42% yield. Isolation of the metalated hydroxyporphyrinoids M3
and M4, as well as free-base dimer H5, mandates that the Wolff
rearrangement competes with several intra- and intermolecular
photochemical reaction pathways.
Since one of the proposed mechanisms for reaction of the
diazobenzo[b]fluorene natural products with DNA involves
alkylation of the nucleic acid substrate,14 diazo-oxochlorins Ni1
and Cu1 were photolyzed in the presence of tetrahydrofurfuryl
alcohol. The five-membered cyclic alcohol resembles the
backbone of biological substrates based on a carbohydrate
scaffold (e.g., DNA, RNA), as well as the aminoglycoside
antibiotics (e.g., neomycin B) which are widely used for
the treatment of a variety of infections, including tuberculosis
and pneumonia.63 In this latter case, a successful adduct may
have potential as an optical probe for mechanistic drug/cell
interactions.
When Ni1 and Cu1 are photolyzed in the presence of
tetrahydrofurfuryl alcohol, substrate adducts Ni2c (28%) and
Cu2c (16%) are isolated as polar porphyrinoids, along with the
expected Ni3 (35%) and Cu3 (55%) products from a possible
H-atom abstraction pathway (experiments 3 and 7, Table 1).
The presence of Ni3 and Cu3 in pronounced yields indicates
that carbene quenching by purported H-atom abstraction (Vide
infra) is strongly competitive with substrate-adduct formation.
X-ray Characterization of Photoproducts. Addition of nu-
cleophilic substrate clearly mitigates the observed product
distribution. Molecular structures of pyrrole ring-contracted
porphyrinoids that contain butoxy and tosyl ester functionality
on the porphyrinoid ring periphery are illustrated in Figure 2.
The three molecular structures each exhibit strict planarity of
Broadband Photolysis of Diazo-oxochlorins
photolysis product yield (%)
expta
M1
substrate
M2a
M2b
M2c
M3
M4
H5
1
2
3
4
Ni1
BuOH (a)
Ts-NH-NH2 (b)
FurfurylOH (c)
-
16
29
6
35
12
76
12
11
28
trace 76
5
6
7
8
Cu1 BuOH (a)
Ts-NH-NH2 (b)
14
43
18
55
6
6
60
6
13
FurfurylOH (c)
16
66
9
H1
BuOH (a)
34
10
42
10
a Photolysis experiments: expt 1, 15 mg/20 mL, CH2Cl2:a 1:4 (v/v),
9 h; expt 2, 15 mg/20 mL, CH2Cl2:b (10 equiv), 9 h; expt 3, 15 mg/20
mL, CH2Cl2:c 1:4 (v/v), 9 h; expt 4, 15 mg/20 mL, CH2Cl2, 9 h; expt 5,
20 mg/20 mL, CH2Cl2:a 1:4 (v/v), 6 h; expt 6, 20 mg/20 mL, CH2Cl2:b
(10 equiv), 6 h; expt 7, 20 mg/20 mL, CH2Cl2:c 1:4 (v/v), 6 h; expt 8,
20 mg/20 mL, CH2Cl2, 6 h; expt 9, 20 mg/20 mL, CH2Cl2:a 1:4 (v/v),
9 h; expt 10, 10 mg/10 mL, CH2Cl2, 9 h.
concentrated H2SO4 produces the free-base analogue (H1)
straightforwardly in 90%.
Photochemistry. In the presence of nucleophiles (1-butanol,
tosylhydrazine, tetrahydrofurfuryl alcohol), photolysis of diazo-
oxochlorins (M1) in dichloromethane solution yields four
molecular products upon nitrogen extrusion (Scheme 1). These
have been isolated and characterized as the remarkable Wolff-
rearranged azeteoporphyrin (M2a-c, 16-28%), the bimolecu-
larly derived 2-hydroxyporphyrin (M3, 29-55%), and the
intramolecular exocyclic ring-containing hydroxyporphyrinoid
(M4, 6-76%), as well as a dimerization product (H5, 10%) in
the case of the free-base derivative only. The observed product
ratios are strongly influenced by the concentration of nucleophile
in the reaction (Table 1). For photolysis of Ni1 and Cu1
undertaken in the dichloromethane solution in the presence of
nucleophillic substrates (experiments 1-3, 5-7, and 9, Table
1), the unprecedented nucleophile adduct is isolated as a key
product, along with the 2-hydroxyporphyrin (M3) or the
intramolecular ring-addition product (M4). Depending upon
reaction conditions, one of these latter two species is the primary
(63) Quader, S.; Boyd, S. E.; Jenkins, I. D.; Houston, T. A. J. Org. Chem.
2007, 72, 1962.
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Diversifying Photochemical Reactivity of Diazo-oxochlorins
A R T I C L E S
Figure 2. X-ray crystal structures of photoproducts H2a, Cu2a, and Cu2b. For Cu2a and Cu2b, H-atoms are omitted for clarity.
the π-conjugated macrocycle. The observation is notable since
Cu-containing porphyrinoids are often weakly distorted from
planarity.64 These findings are in agreement with our com-
munication52 in which the planar methanol adduct was reported
to be generated under similar conditions, further supporting the
proposal that the four-membered azete ring dictates the con-
formation of the porphyrinoid product. For Cu2a, the Cu-Nazete
distance is 1.887(3) Å, shorter than the remaining Cu-N bonds
in the center of the macrocycle (1.93-2.00 Å) but very similar
to the Cu-Nazete distance of 1.889(3) Å of the methoxy ester
analogue.52 The X-ray structure of H2a reveals similar structural
parameters and the additional insight that the butyl group is
disordered over two sites (ratio 88:12). The structures in Figure
2 illustrate that, for Cu2a and H2a, 1-butanol attacks the ketene
intermediate via the O-H bond, while for Cu2b, tosylhydrazine
adds through the nitrogen lone pair, indicating the tolerance of
the ketene reaction to different electronic nucleophiles. Under
comparable photolysis conditions, tetrahydrofurfuryl alcohol
adds to the chlorin periphery in a manner similar to that observed
with 1-butanol, resulting in an X-ray structure analogous to those
of the ester adducts (Figure 3). The molecular structure of Cu2c
also exhibits a short Cu-Nazete distance of 1.900(4) Å charac-
teristic of the unusual azeteoporphyrin, while the remaining
Cu-N bonds range between 1.93 and 2.00 Å and are more
typical of porphyrinoid structures.64,65
Figure 3. Top: X-ray crystal structure of Cu2c (H-atoms are omitted for
clarity). Bottom: Tetrafurfuryl alcohol substrate c and analogues.
In addition to the remarkable scaffolds of the substrate
adducts, the molecular structures of monomeric (Cu4) and
dimeric (H5) intramolecular ring-addition products are shown
in Figure 4. The connectivities of the individual porphyrinoid
units are identical and vary only in the hybridization of the
perimeter functionality (OH vs CdO). Photoinduced radical
addition across the meso-phenyl ring produces the intramole-
cluarly quenched monomer, which can further react by either
H-atom abstraction or bimolecular radical-radical coupling to
generate Cu4 or H5, respectively. Crystallographically, por-
phyrin Cu4 is disordered over two positions with about 0.86
(64) Henling, L. M.; Schaefer, W. P.; Hodge, J. A.; Hughes, M. E.; Gray,
H. B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1993, C49,
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Chem. 1995, 34, 5073.
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A R T I C L E S
Ko¨pke et al.
Figure 4. X-ray structure of photoproduct Cu4, exibiting exocyclic ring
formation (left), and dimeric free-base photoproduct H5, which derives from
intramolecular quenching and subsequent radical-radical coupling reaction
(right). The phenyl rings in H5 have been omitted for clarity.
Figure 6. Comparison of normalized electronic spectra of photoproducts
H2a (s) and H5 (- - -) in CH2Cl2.
identical. The λmax (Soret) ranges between 404 and 407 nm and
λmax (Qx) between 594 and 598 nm for Ni2a-c, while for
Cu2a-c, λmax (Soret) ) 412 nm and λmax (Qx) is centered at
603-605 nm. In light of the variability in substrate, the
insensitivity of the electronic properties to substrate addition
indicates that the 20-electron π-system is uncoupled from the
Cꢀ position of the azete ring, as predicted for chlorins by the
Gouterman model.67
Comparison of the electronic spectra of H2a and the dimeric
structure H5 (Figure 6) reveals a pronounced broadening of both
the Soret and Q-band features and a marked red-shift of the
lowest energy components of the electronic spectral envelope.
The Soret band maximum is nearly degenerate with the H2a
monomer; however, a second feature of comparable intensity
is now predominant at λ ) 457 nm. Accompanying these
transitions are at least five clearly defined absorption maxima
at λ ) 565, 612, 642, 679, and 715 nm, spanning a Q-region of
∼5000 cm-1. These electronic properties are a direct conse-
quence of the new exocyclic rings in each monomer formed by
electrophilic aromatic substitution of the carbene intermediate
with the adjacent meso-phenyl group, as well as the short
intermacrocyle distance (3.03-4.11 Å) caused by the direct
Cꢀ-Cꢀ bond (1.63 Å) between the monomers (i.e., exciton
coupling).
Figure 5. Normalized electronic spectra of Wolff-rearranged photoproducts
Ni2a (- · -), Cu2a (s), and H2a (- - -) in CH2Cl2.
ether solvent molecule per formula unit. The X-ray structure of
the free-base dimer H5 reveals that the carbons connecting the
two macrocycles possess sp3 hybridization and are the central
atoms of a distorted tetrahedron, with this 1.63 Å bond
considerably elongated relative to the remaining three C-C
distances (1.50-1.54 Å). The structure also includes the solvents
ether and dichloromethane in the formula unit. Two ether
molecules are disordered over a special position, one of which
is additionally disordered with dichloromethane.
Electronic Spectra. The normalized electronic spectra of Ni2a,
Cu2a, and H2a are shown in Figure 5. These unusual aze-
teoporphyrin products exhibit electronic spectra in CH2Cl2 that
qualitatively resemble those of the corresponding 2-diazo-3-
oxochlorin precursors in energy and intensity, with strong Soret
absorption between λ ) 400 and 415 nm and a prominent Qx
band at long wavelength (λ ) 580-640 nm). The metalated
forms also show a weaker vibronic overtone to higher energy
of Qx, while H2a exhibits the customary Qy band at λ ) 555
nm and associated overtone at λ ) 525 nm. These observed
spectral differences for Ni2a, Cu2a, and H2a are in agreement
with the classical electronic structure description (i.e., symmetry,
orbital degeneracy) of the conjugated 20-electron π-system of
the macrocycle.66 For substrate adducts Ni2a-c and Cu2a-c,
the electronic spectra within the respective series are almost
Aqueous Micelle-Encapsulated Photochemistry. The desire
to impart control over the photoreactivity of the diazo-
oxochlorins, coupled with an interest in moving toward aqueous
solution photochemistry, led to encapsulation of Cu1 into
micelles of 16:0 PEG3 PE. Photolysis (λ g 345 nm) of an
aqueous solution of 0.013 × 10-6 M micelle-encapsulated Cu1
results in isosbestic conversion to a new species with λmax
)
414 and 537 nm within 10 min, which was subsequently
identified and characterized as the hydroxyporphyrin derivative
Cu3 (Figure 7a). In contrast, photolysis of a dichloromethane
solution of 0.016 × 10-6 M Cu1 results in multiple and
consecutive photochemical decay pathways, as evidenced by
the rapid disappearance of the starting material with λmax ) 435
and 620 nm and growth of new features at λmax ) 416, 465,
(67) Gouterman, M. In The Porphyrins; Dolphin, D., Ed.; Academic Press,
(66) Eisner, U.; Linstead, R. P. J. Chem. Soc. 1955, 3749.
Inc: New York, 1978; Vol. III, p 1.
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Diversifying Photochemical Reactivity of Diazo-oxochlorins
A R T I C L E S
Scheme 2. Proposed Mechanism for Photoproduct Formation upon
Irradiation of Cu1
orbital states where the spin-paired electrons can reside: (1) both
electrons occupy the pz atomic orbital on the carbon atom with
an empty in-plane sp2 hybrid orbital (Cu1S′); (2) one electron
each in the pz and the orthogonal sp2 hybrid orbitals, resulting
in an open-shell singlet (Cu1S′′), and (3) a closed-shell, in-
plane sp2 hybrid singlet with the pz orbital unfilled (Cu1S′′′).
Based on ketocarbene electrophilicity and orbital symmetry
arguments, this latter intermediate is not thought to contribute
to product formation from photolysis of diazo-oxochlorins,
unless a considerable structural distortion occurs during the
reaction trajectory. Based on this premise, the electronic
structures and directionalities of the other two states must lead
to three reactions (pathways a-c) that account for the major
products isolated upon photolysis of Cu1. Ketocarbenes are
known to undergo Wolff rearrangement (pathway a) and insert
into chemical bonds (pathway b), as well as to participate in
H-atom abstraction reactions (pathway c). Pathway a requires
that the unoccupied sp2 orbital of Cu1S′ lie in the plane of the
chlorin ring to promote ring contraction, while intramolecular
insertion into the meso-phenyl ring, pathway b, could conceptu-
ally derive from either Cu1S′ or Cu1S′′ (Vide infra).
Figure 7. Photolysis of Cu1 at λ g 345 nm in (a) an aqueous micelle-
encapsulated environment and (b) CH2Cl2. Spectra were monitored in (a)
after 30 s, 60 s, 90 s, 2 min, 4 min, and 10 min of photolysis; spectra were
obtained in (b) at 3, 5, 15, 30, 50, 70, and 120 min photolysis times.
and 638 nm (Figure 7b). The multicomponent reaction and
product distribution mirrors the photochemical solution experi-
ments that lead to a suite of isolated products in Scheme 1,
thereby verifying the presence of primary bimolecular photo-
chemical reaction pathways in free solution.
Discussion
The diverse photochemical product distribution is clearly
symptomatic of competing carbene reaction mechanisms that
depend intimately upon the presence of substrate. Photolysis
of M1 leads to immediate loss of N2 and formation of a carbene
diradical, as illustrated in Scheme 2 for Cu1. Based on the
absence of a detectable S ) 1 EPR signal at low temperatures,52
aswellascarbene-derivedolefinphotoproductsfromtriplet-triplet
coupling,43,44,68,69 this initial species (ignoring the spin on the
central copper) is tentatively assigned as a singlet spin system
(Cu1S). Within this spin manifold, there exist three possible
Experimentally, broadband photolysis (λ g 345 nm) of both
free-base and metalated diazo-oxochlorins leads to formation
of the unusual Wolff ring-contracted photoproducts via substrate
addition (pathway a). This suggests that the electronic structures
(68) Nazran, A. S.; Griller, D. J. Am. Chem. Soc. 1984, 106, 543.
(69) Tomioka, H.; Hirai, K.; Nakayama, T. J. Am. Chem. Soc. 1993, 115,
1285.
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A R T I C L E S
Ko¨pke et al.
and local periphery polarizations of the corresponding carbene
intermediates are very similar. Since the high-energy Cu1S′
intermediate has a vacant back lobe of the sp2 hybrid orbital in
the plane of the pyrrole ring, donation from the adjacent C-C
σ-orbital to the electron-deficient carbene facilitates the Wolff
rearrangement.70
operative during the photochemical reaction of the open-shell
singlet diradical (Cu1S′′) of these diazo-oxochlorins. The
supposition is supported by the observation that only metalated
diazo-oxochlorins form hydroxylated products such as Cu3 and
Ni3, while the corresponding free-base analogue is never
observed.
Although the reaction pathways described in Scheme 2
provide a qualitative understanding of the possible origins of
the different photoproducts, they do not give information about
the energetics of the intermediate or address what drives the
product distribution. Pathways a and c are clearly influenced
by substrate. The presence of a nucleophilic solution substrate
channels reactivity toward isolable Wolff product, albeit in
modest yields (∼10-30%). Under these same substrate condi-
tions (Table 1), significant quantities of hydroxyporphyrin
(∼5-35%) are also obtained, deriving pathway c, whereas in
the absence of nucleophilic substrate, intramolecular quenching
by addition to the meso-phenyl ring (pathway b) dominates
(66-76%). The ability of the substrate to trap the Wolff-
rearranged ketene and the hydroxypophyrin via Cu1S′ and
Cu1S′′, respectively, leads to their presence as isolable products.
Interestingly, although both substrate-dependent pathways a and
c appear inoperative in the absence of nucleophile, it is the
phenyl ring addition and hydroxyporphyrin products, from
pathways b and c, respectively, that most obviously compete
based on product yields (cf. Table 1, expts 5-8), with the Wolff
species appearing somewhat invariant under substrate conditions.
In light of this chemical interplay, we attribute reaction pathway
b and intramolecular exocyclic ring formation to intermediate
Cu1S′′.
Since Cu1 is formally reduced during transformation to Cu3
along pathway c, we postulated that substrate oxidation may
be the key parameter required for generation of Cu3. This would
explain why formation of Cu3 is diminished during photolysis
in neat dichloromethane. To support this hypothesis, Cu1 was
photolyzed in the presence of tert-butyl alcohol. Since tertiary
alcohols are more resistant to oxidation and are generally less
nucleophilic, formation of Cu3 should be limited. In fact,
photolysis of Cu1 in the presence of tert-butyl alcohol under
conditions similar to those described for substrates a-c gave
no Cu3 and instead gave the intramolecular phenyl addition
product Cu4 in 51% yield, mirroring the result obtained in the
absence of substrate. This strongly suggests that the major
driving force for reaction pathway c in Scheme 2 is the tendency
of the substrate toward oxidation. Therefore, reduction of the
photogenerated carbene porphyrinoid with subsequent keto-enol
tautomerization must account for the formation of Cu3. To
further support this conclusion, Cu1 was photolyzed in the
presence of the non-nucleophilic reducing agent 1,4-cyclohexa-
diene, which should enhance the formation of Cu3 if the
proposed mechanism is valid. Indeed, photolysis of Cu1 in the
presence of 1,4-cyclohexadiene gives 55% yield of Cu3 and
no Cu4. These results lead to the conclusions that the photo-
prepared carbene intermediates are capable of substrate oxidation
and the observed photoproduct ratios are related to the oxidation
potential of the specific substrate.
Along pathway b, both structurally characterized photoprod-
ucts, Cu4 and free-base derivative H5, show exocyclic ring
formation, which also results from electrophilic attack/insertion
by the deficient sp2 orbital. For this primary step, two possible
routes are viable. The first involves insertion of the electron-
deficient orbital into the C-H bond at the ortho position of the
transiently planar ring, as is customary for carbene insertion
into aliphatic hydrocarbons.42,43 The second is defined by
electrophilic attack upon the π-system of the meso-phenyl ring.71
For a bimolecular event, the latter pathway is likely preferred;
however, in the constrained geometry of the macrocycle, sp2-π
(phenyl) orbital overlap is compromised due to the requirement
for partial ring rotation to relieve orthogonality. This leaves the
precise mechanism for exocyclic ring formation somewhat
ambiguous based solely on product distribution.
Under this general scheme, electrophilic attack on the meso-
phenyl ring by the carbene leads to transient radical formation
on both the macrocycle and the compromised phenyl ring. For
the metalated chlorins (e.g., Cu4), H-atom migration to the
macrocycle re-aromatizes the phenyl ring and generates the keto-
chlorin product. This species can then undergo a keto-enol
tautomerization72 to yield the isolated exocyclic ring-containing
hydroxyl species Cu4. In contrast, for the free-base derivative,
loss of an H-atom (macroscopically as H2) re-aromatizes the
ring, producing a monoradical on the macrocycle that can
undergo bimolecular radical-radical coupling to yield ho-
modimer H5. The sensitivity of the keto-enol tautomerization
to the presence of central metal ion (Vide infra)72 may be a
differentiation point between these products.
Within the theme of the radical reactivity above, the locally
separated but spin-paired electrons of the open-shell singlet of
Cu1S′′ can also participate in triplet carbene-like reactivity (i.e.,
H-atom abstraction) with substrate, resulting in the hydroxylated
products Cu3 of pathway c. Despite the apparent insensitivity
of product formation to the central metal for pathways a and b,
it is well known that π-electron distribution across the macro-
cycle can play an important role in the reactivity of the
porphyrinoid periphery.73 For instance, the relatively electro-
negative metal ions, Cu(II) and Ni(II), have been shown to
function as activating groups for nucleophilic reactions at the
porphyrin periphery.74 For metalated 2-hydroxy-5,10,15,20-
tetraphenylporphyrins (e.g., Cu3), this results in a dramatic
difference in the keto-enol tautomer equilibrium relative to the
corresponding free base, even in the solid state.72,75 Here, the
Cu(II) and Zn(II) analogues were found to exist almost
exclusively as hydroxyporphyrins.72 On the basis of this detailed
report, we propose that such a keto-enol equilibrium is also
(70) McMahon, R. J.; Chapman, O. L.; Hayes, R. A.; Hess, T. C.; Krimmer,
H. P. J. Am. Chem. Soc. 1985, 107, 7597.
(71) Abramovitch, R. A.; Alexanian, V.; Smith, E. M. J. Chem. Soc., Chem.
Commun. 1972, 893.
Finally, photolysis of Cu1 in aqueous media containing 16:0
PEG3 PE micelles reveals isosbestic conversion of Cu1 to one
major product at 10 °C, which is in great contrast to the more
diverse photochemical decay of Cu1 in dichloromethane under
similar conditions (Figure 7). Micelle encapsulation is certainly
expected to diminish the possibility of dimer formation, which
is in agreement with the observed spectroscopic data for the
(72) Crossley, M. J.; Harding, M. M.; Sternhell, S. J. Org. Chem. 1988,
53, 1132.
(73) Catalano, M. M.; Crossley, M. J.; Harding, M. M.; King, L. G. J. Chem.
Soc., Chem. Commun. 1984, 1535.
(74) Crossley, M. J.; King, L. G.; Pyke, S. M. Tetrahedron 1987, 43, 4569.
(75) Crossley, M. J.; Field, L. D.; Harding, M. M.; Sternhell, S. J. Am.
Chem. Soc. 1987, 109, 2335.
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Diversifying Photochemical Reactivity of Diazo-oxochlorins
A R T I C L E S
Acknowledgment. The support of Indiana University and the
Argonne National Laboratory is gratefully acknowledged. Chem-
MatCARS Sector 15 is principally supported by the National
Science Foundation/Department of Energy under grant number
CHE-0535644. Use of the Advanced Photon Source was supported
by the U.S. Department of Energy, Office of Science, Office of
Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.
photolyzed micelle solution. More specifically, based upon
electronic spectral analysis, Rf value comparison, and mass
spectroscopy after photolysis, sequestration appears to drive the
reaction along pathway c, forming Cu3, likely via oxidation of
the micelle by Cu1S′′.
Conclusion
Photolysis of diazo-oxochlorins leads to pyrrole ring contrac-
tion and substrate trapping (Wolff rearrangement) of the rare
azeteoporphyrinoids via the spin-paired singlet carbene, while
the open-shell singlet state leads to unusual exocyclic ring
formation and substrate oxidation by H-atom abstraction,
generating hydroxyporphyrin products. Choice of reaction
pathway is to some extent under substrate control, providing a
manifold for variable chemical reactivity. Aqueous photochem-
istry is also realized upon micelle encapsulation of the starting
diazo-oxochlorin, where the products are once again driven by
the environment of the micelle interior. In general, the ability
to influence and modulate substrate addition, alkylation, or
oxidation using these photoreactive chromophores leads to
potential for such constructs as biological labeling or damaging
motifs in the absence of co-reagents or O2.
Supporting Information Available: Details about X-ray
structure data collection, structure solution, and refinement for
Cu2a-c, H2a, Cu4, and H5, including CIF files. This material
is available free of charge via the Internet at http://pubs.acs.org.
The crystallographic data for the structures reported herein have
been also deposited with the Cambridge Crystallographic Data
Centre as CCDC Nos. 668799 (Cu4), 668800 (H2b), 668801
(Cu2b), 668802 (H5), 668803 (Cu2a), and 668804 (Cu2c).
Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Rd., Cambridge CB2 1EZ, UK (fax (+44)
1223-336-033; E-mail deposit@ccdc.cam.ac.uk).
JA800094E
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