Meso-arylporpholactones and their reduction products

Article abstract of DOI:10.1021/jo300963m

The rational syntheses of meso-tetraaryl-3-oxo-2-oxaporphyrins 5, known as porpholactones, via MnO₄^--mediated oxidations of the corresponding meso-tetraaryl-2,3-dihydroxychlorins (7) is detailed. Since chlorin 7 is prepared from the parent porphyrin 1, this amounts to a 2-step replacement of a pyrrole moiety in 1 by an oxazolone moiety. The stepwise reduction of the porpholactone 5 results in the formation of chlorin analogues, meso-tetraaryl-3-hydroxy-2-oxachlorin (11) and meso-tetraaryl-2-oxachlorins (12). The reactivity of 11 with respect to nucleophilic substitution by O-, N-, and S-nucleophiles is described. The profound photophysical consequences of the formal replacement of a pyrrole with an oxazolone (porphyrin-like chromophore) or (substituted) oxazole moiety (chlorin-like chromophore with, for the parent oxazolochlorin 12, red-shifted Q_x band with enhanced oscillator strengths) are detailed and rationalized on the basis of SAC-CI and MNDO-PSDCI molecular orbital theory calculations. The single crystal X-ray structures of the porpholactones point at a minor steric interaction between the carbonyl oxygen and the flanking phenyl group. The essentially planar structures of all chromophores in all oxidation states prove that the observed optical properties originate from the intrinsic electronic properties of the chromophores and are not subject to conformational modulation.

Full text of DOI:10.1021/jo300963m

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Article
meso-Arylporpholactones and their Reduction Products
Christian Brueckner, Junichi Ogikubo, Jason R. McCarthy, Joshua Akhigbe, Michael A
Hyland, Pedro Daddario, Jill L Worlinsky, Matthias Zeller, James T Engle, Christopher John
Ziegler, Matthew J. Ranaghan, Megan Nollenberger Sandberg, and Robert Richards Birge
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300963m • Publication Date (Web): 26 Jun 2012
Downloaded from http://pubs.acs.org on July 1, 2012
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meso-Arylporpholactones and their Reduction Products
Christian Brückner†,*, Junichi Ogikubo†, Jason R. McCarthy†,‡, Joshua Akhigbe†, Michael A. Hyland†,
Pedro Daddario†, Jill L. Worlinsky†, Matthias Zeller§, James T. Engle,% Christopher J. Ziegler,%
Matthew J. Ranaghan&, Megan N. Sandberg†, and Robert R. Birge†,&
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Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States. Department
of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269-3125, United States.
Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555-
3663, United States. Department of Chemistry, University of Akron, Akron, OH 44325-3601, United
States.
RECEIVED DATE
Oxazolochlorins 6. Oxazolochlorins 5: Akhigbe, J.; Haskoor, J.; Zeller, M.; Brückner, C. Chem. Commun.
2011, 47, 8599–8601.
† University of Connecticut, Department of Chemistry
‡ Current address: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114,
United States.
§ Youngstown State University
% University of Akron
& University of Connecticut, Department of Molecular and Cell Biology
* Author to whom correspondence should be addressed: Fax: (+1) 860 486-2981; Tel: (+1) 860 486-2743;
e-mail: c.bruckner@uconn.edu
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Abstract. The rational syntheses of meso-tetraaryl-3-oxo-2-oxaporphyrins 5, known as porpholactones,
via MnO4–-mediated oxidations of the corresponding meso-tetraaryl-2,3-dihydroxychlorins (7) is detailed.
Since chlorin 7 is prepared from the parent porphyrin 1, this amounts to a 2-step replacement of a
pyrrolemoiety in 1 by a oxazolone moiety. The step-wise reduction of the porpholactone 5 results in the
formation of chlorin analogues, meso-tetraaryl-3-hydroxy-2-oxachlorin (11) and meso-tetraaryl-2-
oxachlorins (12). The reactivity of 11 with respect to nucleophilic substitution by O-, N-, and S-
nucleophiles is described. The profound photophysical consequences of the formal replacement of a
pyrrole with an oxazolone (porphyrin-like chromophore) or (substituted) oxazole moiety (chlorin-like
chromophore with, for the parent oxazolochlorin 12, red-shifted Qx band with enhanced oscillator
strengths) are detailed and rationalized on the basis of SAC-CI and MNDO-PSDCI molecular orbital
theory calculations. The single crystal X-ray structures of the porpholactones point at a minor steric
interaction between the carbonyl oxygen and the flanking phenyl group. The essentially planar structures
of all chromophores in all oxidation states prove that the observed optical properties originate from the
intrinsic electronic properties of the chromophores and are not subject to conformational modulation.
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Introduction
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meso-Tetraarylporphyrins 1 and their metal complexes are used in a number of model compounds for
naturally occurring porphyrinic cofactors or light-harvesting systems.1 The great popularity of 1 arises
from their straight-forward syntheses and the availability of a wide variety of aryl-functionalized
derivatives.2
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In a seminal contribution by Crossley and King more than 25 years ago,3 it was recognized that
oxidation of β-substituted porphyrins, such as dione 6 (prepared from 1 via 2, 3, or 4), can lead to the loss
of one β-carbon and the formal replacement of the porphyrinic β,β’-bond by a lactone moiety, forming
porpholactone 5 (Scheme 1).
Ar
Ar
NO2
NH
N
N
NO2 or
Ar
Ar
N
AgNO3, I2
HN
Ar
2
1
Ar
[E-benzaldi-
oxamato]Na
NaBH4, Pd-C or
SnCl2, HCl
BzOOH,
OH-
Ar
Ar
OH
NH2
N
N
AgNO3,
AcOH, "
(for Ar = C6F5)
Ar
Ar
3
4
m-CPBA
(for Ar =
2,6-Cl2C6H3)
h!, O2 or
SeO2
1O2
Ar
O
Ar
O
O
NH
N
O
N
m-CPBA
N
Ar
Ar
Ar
HN
6
5
Ar
a Only free bases are shown but some transformations may require metal complexation, or
metal insertion takes place during the transformation.
Scheme 1. Literature-known syntheses of porpholactone 5.a
One other serendipitous finding five years later identified strongly oxidizing reaction conditions
(AgNO3 in refluxing acetic acid containing oxalate) that were suitable for converting porphyrin 1 (with Ar
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= C6F5) directly into a porpholactone.4,5 However, the latter reaction is not general since it is only
applicable toward the synthesis of meso-tetrakis(pentafluorophenyl)porpholactone. The method also
requires extensive chromatography to separate the porpholactone from the starting material and numerous
other non-polar ‘over-oxidized’ byproducts.4,5 Additional specialized reaction pathways toward
porpholactones have been discovered since, such as the singlet oxygen oxidation of β-aminoporphyrin 4
(Scheme 1).6 Select oxidations of dione 6 also lead to porpholactones, perhaps shedding light on a
possible reaction mechanism toward the formation of porpholactones 5.7 Porpholactones also appeared as
adventitious products in a variety of oxidation reactions of β-derivatized porphyrins.7-9
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Porpholactones have been demonstrated to be of practical value: The Fe(III) and Fe(IV)=O+ complexes
of meso-tetrakis(2,6-dichlorophenyl)-substituted porpholactone were used as model compounds for
naturally occurring chlorin-type prosthetic groups.6 The catalytic activity of the Fe(III)Cl and Mn(III)Cl
complexes of meso-tetrakis(phenyl)porpholactone with respect to olefin epoxidation and sulfide oxidation
reactions were tested.10,11 [meso-Tetrakis(pentafluorophenyl)porpholactonato]Pt(II) is a promising
component in pressure sensitive paints,12 allowing the imaging of air flow around objects.13 This complex
can also be utilized as a high pH sensor in the range of pH 11.5–13.14 Despite their increasing utility and
the emergence of their unique reactivity, no full account on the rational, general, and high-yielding
synthesis of meso-tetraarylporpholactones has been published to date. In the first part of this report, we
will fill this gap by following on our communication.15
We previously detailed the OsO4-mediated β,β’-dihydroxylation of meso-tetraarylporphyrin 1 and closely
related porphyrin derivatives to produce the corresponding meso-tetrakis-2,3-dihydroxy-2,3-chlorin 7.14,16-
19,20 This reaction was adopted by other groups, providing a range of dihydroxychlorins.10,11,21-23 We further
demonstrated the versatility of the chlorin diols as starting material for the preparation of porphyrinoids
containing non-pyrrolic building blocks using our versatile ‘breaking and mending’ strategy.9,14-18,24,25 The
synthesis of porpholactones via the MnO4–-mediated oxidation of the known meso-tetraaryl-2,3-
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dihydroxychlorins also follows this strategy. We will also present the structural description of free base
and Zn(II) porpholactones using single crystal X-ray diffraction structure elucidation.
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In the second part of this report we present a comprehensive account of the hydride-mediated reduction
reactions of porpholactones 5 to chlorin-like 2-oxachlorins (also known as oxazolochlorins) containing
hemiacetal, acetal, and ether functionalities. Owing to their intense absorbance at wavelengths > 650 nm,
the optical window of tissue,26 chlorins (β,β’-dihydroporphyrins) are superior to porphyrins in all
applications in which light needs to penetrate tissue, such as the photodynamic therapy (PDT) of tumors.27
In addition, many naturally occurring light-harvesting chromophores are chlorins.28 In part owing to these
applications, the generation of chlorins by total synthesis or by conversion of porphyrins has become a
central topic in current porphyrin chemistry.29
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We previously presented an isolated example of a reduced porpholactone derivative, hemiacetal
3-hydroxy-3-oxachlorin 11a, in a comparative study of chlorins,30 and we demonstrated that this
compound possesses high photodynamic efficacy in vivo in a murine tumor model.31 We also identified an
adventitious side-product in the oxidative transformations of the silver(II) complex of dihydroxychlorin 7
as an [2-ethoxy-2-oxachlorinato]Ag(II) complex (11aAg).8,32 Lastly, an oxazolochlorin monomer and
dimer formed as products of an intramolecular Cannizzaro reaction of free base secochlorin bisaldehyde
8aH2.9 However, in spite of their use or occurrence on several occasions, no full synthetic paper
describing their rational syntheses has been reported to date. This will be provided herein, and we will
also provide chemical evidence that might rationalize the high biological activity of the hemiacetal.31
In the final section of this manuscript, we will contrast the UV-visible absorption and fluorescence
emission properties of the free base and Zn(II) complexes of the 2-oxaporphyrin and 2-oxachlorin against
each other and against the properties of the parent porphyrin 1a and 2,3-dihydroxychlorin 7aH2. The
observed trends in the optical spectra are rationalized on the basis of SAC-CI and MNDO-PSDCI
molecular orbital theory calculations. Thus, this contribution reveals the synthesis and detailed physical
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and chemical description of a chlorin-like stable family of chromophores that is readily accessible and for
which a number of applications can be foreseen.
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Results and Discussion.
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Synthesis of Porpholactones. Oxidation of dihydroxychlorins 7 with MnO4– produced porpholactone 5
in a single step (Scheme 2). The source of MnO4– can either be an excess of powdered KMnO4 suspended
at ambient temperature in an organic solvent (toluene, CH2Cl2, CHCl3, THF) in the presence of the phase-
transfer agent 18-crown-6, KMnO4 heterogenized on silica gel,33 or, most conveniently, the use of one to
five equivalents of cetyltrimethylammonium permanganate (CTAP)34 in CH2Cl2.
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Ar
Ar
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OsO2(py)2
O
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M
Ar
M
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8
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7xM
9a
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2. H2S
CTAP
Ar
Ar
M
O
OH
OH
KMnO4/18-C-6
or
CTAP, CH2Cl2
O
N
N
Ar
M
Ar
5xM
5aAg
Ag(OAc),
py, !
IO4-silica
Ar
Ph
CO2H
CO2H
CHO
CHO
N
N
M
Ar
Ph
10 (not observed)
M = H2, ZnII, NiII, PtII, AgII
x: a, Ar = C6H5
b, Ar = 4-i-Pr-C6H4
c, Ar = 4-t-Bu-C6H4
e, Ar = 4-OCH3
d, Ar = 3,4,5-MeO-C6H2
f, Ar = 4-CF3
g, Ar = C6F5
Scheme 2. Synthesis of porpholactones 5 by oxidation of 2,3-dihydroxychlorins 7
The work-up of the reaction is simple. Filtration of the crude mixture through a plug of diatomaceous
earth removes the brown, flocculent to pasty manganese oxides. Short column chromatography and
crystallization of the porpholactone isolates the product as crystalline materials in up to 90% yields. The
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reaction times vary, depending on the concentration (and solubility) of the dihydroxychlorin and the
number of equivalents of CTAP (or phase transfer agent) used, and range from 30 min to 12 h. The
addition of several smaller portions of oxidant under TLC control to monitor the consumption of the
starting material proved to be beneficial. Large excesses of oxidant, elevated temperatures or prolonged
reaction times hasten the degradation of the macrocycles, as indicated by the loss of the Soret band in the
UV-visible spectra of the reaction mixtures, and low isolated yields of the desired porpholactones.
We recently described the isolation of the dihydroxychlorin osmate esters 8, the primary products from
the reaction of porphyrin 1 with OsO4.19 The osmate esters are also susceptible to CTAP oxidation to the
corresponding porpholactones but the reaction is slower than the reaction of the corresponding alcohols,
and the fate of the osmium is not clear. Given the high toxicity of OsO4 that potentially forms as a side
product,35 the oxidation of the diol is given preference over the oxidation of the corresponding osmate
ester. We reported the CTAP oxidation of the osmate ester of meso-tetrakis(pentafluorophenyl)-2,3-
dihydroxychlorin 7gH2.14 The reason for this was that the corresponding diol could at the time not be
prepared. Since then, we have reported a method for the preparation of the 7gH2,36 and we found that the
oxidation of this diol is faster and cleaner than the oxidation of its osmate ester. Also, we will report here
that the use of permanganate heterogenized on silica gel offers a very convenient and clean way of
generating this meso-tetrakis(pentafluorophenyl)porpholactone 5gH2 (and it allows facile recovery of
starting material). In general, however, the yields of this reaction are very low (25–30% are typical)
compared to the yields obtained from oxidation of other tetraaryldihydroxychlorins.
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The isolation of the porpholactones by silica gel column chromatography is much facilitated by their
lower polarity compared to the corresponding dihydroxychlorins. Their identification is simplified by
their characteristic mass and NMR spectra, indicative of the loss of one carbon from the porphyrin
framework, the loss of axial symmetry, and the presence of a carbonyl group. As noted previously,3,4 the
UV-visible spectra of free base porpholactones are surprisingly porphyrin-like, while those of their metal
complexes are metallochlorin-like (to be detailed below).
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We consider this methodology toward porpholactones to be fairly general. It is applicable to the
oxidation of free base dihydroxychlorin 7, its Ni(II), Zn(II), Ag(II), and Pt(II) complexes, to diol chlorins
carrying a variety of electron-donating and -withdrawing meso-phenyl substituents,14 and 5,15-diphenyl-
2,3-dihydroxychlorin 14 (see below). We previously also demonstrated the applicability of this method to
the synthesis of dithiaporphyrin- and porphyrin N-oxide-based porpholactones.17,18 As also shown
previously,6,10,11,12 additional metalloporpholactones are available through metal insertions into the free
bases using standard methods (using conventional and microwave heating).
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The exact mechanism of formation of the porpholactones remains unclear. Permanganate oxidation of
dihydroxychlorin 7 suggests the formation of secochlorin biscarboxylate 10. In fact, Crossley already
surmised that the as yet unobserved secochlorin 10 is the immediate precursor to porpholactone 5.3 Other
reactions that reasonably can be expected to produce the biscarboxylate species also generate
porpholactones. For instance, an attempt to insert silver ion into free base bisaldehyde 9 (using excess
Ag(I) in pyridine, heat) formed [porpholactonato]Ag(II) 5Ag in mediocre yield (~20%). Independent
evidence points toward 2,3-dioxochlorins of type 6 to be the key intermediates in the conversion of
porpholactones.7,18 Since porpholactones frequently also appear as adventitious (by)products in a number
reactions that treat (β-derivatized) porphyrins under a variety of oxidizing conditions,3,4,7,8 one may regard
porpholactones as the thermodynamic sink in the β,β’-oxidative degradation pathway of porphyrins. As
such, it can be reasonably assumed that multiple pathways lead to this product.
Structural Aspects of Porpholactones. The crystal structures of [porpholactonato]Mn(III)Cl,10
Fe(III)Cl,6 Cu(II),7 and Ni(II)7 complexes are known. Thus, the connectivity of the porpholactones is not
in question. However, the crystal structures of free base porpholactone 5aH2 and its Zn complex 5aZn are
interesting with respect to a number of other aspects (Figure 1A). The structural relationship of 5aH2 to
the corresponding porphyrin 1aH237 is highlighted by the fact that both structures possess essentially
isostructural unit cell parameters: same space group P , with the cell dimension varying by only ~1%
1
when comparing the room temperature structure of 1aH2 to the structure of 5aH2 determined at 100 K.
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The chromophore of porpholactone 5aH2 is, analogous to that of porphyrin 1aH2, in effect planar with
only a minor waving deformation (wav(x)) of the two opposing pyrrole moieties that is likely caused by
the repulsion of the two inner hydrogens.38 Like the metalloporpholactone crystal structures described
today (see below), the free base porpholactone structure is highly disordered with respect to the relative
position of the lactone moiety. In 5aH2 all 8 possible positions/orientations are occupied, albeit in a non-
statistical manner (for details, see ESI). While this highlights the structural equivalency of the
replacement of a β,β’-bond by a lactone moiety, it also diminishes the significance of small bond lengths
and angles differences. We therefore will consider herein mostly general structural trends.
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A comparison of the Ni(II), Cu(II), Fe(III), and Mn(III) complexes of porphyrins39 and
porpholactones6,7,10 show also their overall similarity with respect to the respective overall macrocycle
conformation. The C=O bond length in the zinc porpholactone 5aZn is 1.26 Å and the C-O bond length is
1.40 Å. The corresponding bond lengths in the Mn(III)Cl complex of 5a are 1.20 and 1.40 Å.10
Figure 1B shows a side view of the macrocycles of [porpholactonato]Zn(II) 5aZn and its porphyrin
analogue 1pyZn ([meso-tetrakis(4-pyridyl)porphyrinato]Zn(pyridine))40 (and the diphenylporpholactone
15-II-Zn, described below). The zinc ion sits in all complexes slightly out of plane, drawn toward the side
of the axially coordinated pyridine. This is normally observed for square pyramidal zinc(II) porphyrin
complexes.39 Most notably when comparing the conformations of the macrocycles in 5aZn and 1pyZn,
the oxazolone moiety is not, as expected, perfectly co-planar with the macrocycle. This deviation may
originate from a steric interaction between the carbonyl oxygen and the flanking phenyl group. A
comparable observation was made for the Cu(II) complex of tetrakisphenylporpholactone.7
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Figure 1. Single crystal X-ray structures of porpholactone 5aH2, [porpholactonato]Zn(py) 5aZn, 2-
oxachlorin 12H2, 3-methoxy-2-oxachlorin 13-OMe, and [diphenylporpholactonato]Zn(py) 15-II-Zn. A.
Oblique views; all solvates, disorder, and hydrogen atoms attached to sp2-carbons removed for clarity. B.
Side view of the porpholactones 5aH2 and 15-II-Zn in comparison to an comparable view to the
chromophore of [meso-tetrakis(4-pyridyl)porphyrinato]Zn(pyridine) 1pyZn; meso-aryl substituents,
axially coordinated pyridine (if present), and hydrogen atoms attached to sp2-carbons removed for clarity.
See ESI for details on the crystal structure analyses.
To test whether other experimental evidence can be found for a significant steric interaction between
the lactone carbonyl and the flanking phenyl group, we subjected the known diphenyl-2,3-
dihydroxychlorin 1423 to the CTAP oxidation conditions (Scheme 3). Two isomers of the corresponding
diphenylporpholactone 15 can be formed: 2-oxa-3-oxo structure 15-I-H2, and 3-oxa-2-oxo structure
15-II-H2.
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2
OH
Ph
3
2
5
OH
3
NH
N
4
20
5
N
HN
15
6
7
8
9
14
Ph
CTAP
O
Ph
Ph
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13
14
15
16
17
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21
3O
3
O
2
2
O
NH
N
NH
N
N
N
HN
HN
Ph
15-I-H2
Ph
1:5 ratio
15-II-H2
Zn(II)
15-II-Zn
Scheme 3. Synthesis of diphenylporpholactone regioisomers 15-I-H2 and 15-II-H2.
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The oxidation of diol 14 proceeded smoothly and rapidly, generating a porpholactone product mixture.
1
The H NMR of the porpholactone fraction indicated the presence of two isomers in a ~1:5 ratio (see
ESI). Repeated preparative plate chromatography and recrystallizations (from MeOH/CHCl3) allowed the
isolation of a pure fraction of the majority product but the minority product could not be isolated in pure
and high enough yields to perform a full analysis. 1D and 2D-NMR spectroscopy (see ESI) allowed the
unambiguous assignment of the majority product as the 2-oxo-3-oxa isomer 15-II-H2, that is unaffected
by any steric interaction between the lactone carbonyl and a phenyl group. This was confirmed by single
X-ray crystal structure elucidation of 15-II-Zn, as its pyridine adduct, formed by zinc insertion into the
free base (Figure 1).
The fact that the seemingly less sterically inhibited isomer forms in preference over the other isomer
serves as an indication for the existence of a small but noticeable steric interaction between the carbonyl
and the phenyl group. Most significantly, the macrocycle conformation (Figure 1B) shows that the lactone
moiety is near-perfectly co-planar with the oxazole moiety, and that the macrocycle of 15-II-Zn is overall
significantly more planar than that of the tetraaryl analogue 5aZn. This provides the most convincing
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proof for the rationalization of the non-planar arrangements of the lactone moiety with the porphyrins in
5aH2 and 5aZn on steric grounds.
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In addition, we observed reduced disorder in the structure of 15-II-Zn versus that observed in 5aZn,
and thus can more reliably determine the bond lengths in the oxazolone ring. The C=O lengths in 15-II-
Zn range from 1.106(3) to 1.228(3) Å, while the C-O lengths vary between 1.357(3) to 1.486(8) Å (there
are two independent molecules per unit cell). Compared to the free base porpholactones, these bond
length changes compared to the porpholactone free base support a chlorin rather than a porphyrin-like
electronic structure.
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Step-wise reduction of porpholactone 5aZn. Functional group conversions of the lactone moiety offer
the opportunity to synthesize oxazolochlorins.9,25,30,31 Thus, reduction of the non-polar purple
porpholactone 5aZn with DIBAL-H in dry THF at -78 °C generates in near-quantitative yields a bright
blue-green pigment of much higher polarity (isolated yields ~80%, 1 gram scale; Scheme 4). The
1H NMR spectroscopic signature of this product is lactone-like with two additional signals: One signal of
variable chemical shift assigned to the hydroxy functionality (exchangeable with D2O), and a signal at
3.62 ppm attributed to the proton of the oxazole-moiety (cf. to the pyrrolidine proton of 7aZn at 6.12
ppm)16. The corresponding sp3-carbon signal is observed at 112.1 ppm in the C NMR spectrum. All
13
other analytical and spectroscopic data confirm the structure of the reduction product to be [3-hydroxy-2-
oxachlorinato]Zn 11Zn.
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Ph
O
O
N
3
4
Zn
Ph
5
6
7
5aZn
DIBAL-H, THF, -78°C
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9
Ph
OH
O
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N
N
N
Ph
M
Ph
N
Ph
M = Zn, 11Zn
M = 2H, 11H2
CHCl3, 6N aq HCl
Et3SiH, CH2Cl2, [H+]
Ph
O
N
N
N
N
H
H
Ph
Ph
12H2
Ph
Scheme 4. Step-wise reduction of porpholactones 5.
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The reduction of free base porpholactones (5H2) is complicated by the formation of aluminum-
containing side products. Low valent aluminum species are known to metalate free base porphyrins.41
Therefore, the free base porpholactol 11H2 is best prepared by reduction of the zinc complex 5aZn,
whereby the work-up procedure includes a wash with 6M aqueous HCl that demetalates the product.
The hemiacetal functionality of 11H2 is susceptible to acetal formation under mild conditions.8,9 Hence,
alcohols must be excluded from any isolation and/or manipulation procedure of 11H2/Zn, lest the
formation of the corresponding acetals are desired (see also below).
An acid-catalyzed (BF3⋅OEt2 or Amberlyst 15, H+ form) silane-induced deoxygenation of the lactol
hydroxy group of 11H2 (or 11Zn concomitant with a demetallation reaction) at room temperature
provides a green compound that can be identified as the oxazolochlorin 12H2. The loss of the hydroxyl
group from 11H2 is marked by a decrease in polarity of the product, the appearance of the signals in the
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1H NMR at 6.54 ppm for the two oxazolochlorin protons, accompanied by the signal in the 13C NMR for a
secondary carbon (DEPT) at 76.4 ppm (see ESI).
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8
9
The connectivity of 2-oxachlorin 12H2 could be determined by single crystal X-ray diffraction (Figure
1A). As expected, the chromophore is planar with none of the non-planarity observed in the
porpholactones 5. However, the extraordinary degree of disorder of the molecule in the crystal precludes
any detailed bond length and angle analysis.
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2-Oxachlorin 12H2 is generally sensitive toward (photo-sensitized) oxidation back to porpholactol
11H2. Thus, the compound must be shielded from exposure to light or oxidizing conditions. The oxazole
methylene group is located in a benzylic position with respect to the porphyrinoid aromatic system and α
to an oxygen atom in the oxazole moiety. This group thus is highly activated with respect to, for instance,
carbocation formation, a fact highlighted by an oxidative dimerization reaction of an oxazolochlorin that
is proposed to be an intermediate in the Cannizzaro reaction of meso-phenylsecochlorin bisaldehyde.9 As
a result of this high reactivity, insertion of zinc(II) into 12H2 requires anaerobic conditions. Warming
12H2 with Zn(OAc)2⋅2H2O in degassed warm DMF under N2 leads cleanly to the formation of 12Zn. The
optical properties of the oxazolochlorin derivatives are discussed below.
Attempts at one-step reductions from 5aZn to 12aZn using LiAlH4 or DIBAL-H under more forcing
conditions (large stoichiometric excess, room temperature) failed. These reactions merely lead to the
destruction of the porphyrinic macrocycle without the formation of any major product.
Acetalization of Porpholactol 11H2. The lactol hydroxy group of 11H2 is susceptible to facile acid-
catalyzed nucleophilic substitution by a range of O-, N-, and S-nucleophiles, providing access to a
number of stable chlorin-like derivatives of graded lipophilicity (Scheme 4). A marked nucleophile-
dependent reactivity difference is noted. Exposure of 11H2 to primary, secondary, and tertiary alcohols
results in a rapid reaction that is essentially quantitative after 30 min to 1 h at ambient temperature. The
resulting acetals 13-OR showed all the expected spectroscopic data. Diagnostic for the successful
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formation of acetals containing an α-methylene group, this group shows a diastereotopic splitting. This
can be rationalized by its relative position with respect to the macrocycle plane,32 exposing one of the
methylene protons to a much larger degree to the diatropic ring current than the other. Alkoxy-substituted
morpholinochlorins show a very similar effect.15,16 Bulky alcohols like cholesterol or pregnenolone can
also be attached to the chromophore with ease.
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The crystal structure of 13-OMe, as its Ag(II) complex32 and a phorpholacol acetal dimer9 were
previously characterized by single crystal X-ray diffraction. We present here the structure of 13-OMe as a
proof of connectivity and to complete the series of 2-oxachlorins in three different oxidation states
(together with the 3-oxo- and the 3-hydroxy-2-oxachlorins), but the structure is disordered to a point that
a conformational analysis is meaningless. The conformation of the oxazolochlorin chromophore in the
dimer, however, suggested a certain degree of conformational flexibility, though no major distortions
from planarity were observed.9
Secondary amines required a longer reaction time and azeotropic removal of the water formed (reflux in
benzene with 3 Å mol sieves placed in a Soxhlet apparatus over several days) to push the reaction to
completion. The hemiaminals 13-NR2 showed all the expected spectroscopic and analytical properties,
including the diastereotopic split of the α-methylene protons. We did not succeed in reacting primary
amines with the porpholactols under these or other conditions tested.
The reactivity of primary thiols was very much similar to the reactivity of the corresponding alcohols.
Over time, however, the formation of side products with spectroscopic data suggestive of being the
corresponding sulfoxides appeared (m/z = +16 compared to the expected compound; essentially identical
1H and 13C NMR spectra).
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13-OMe, OR = OCH3
13-OEt, OR = OC2H5
13-OiPr, OR = O-i-C3H7
13-OtBu, OR = O-t-C4H9
13-OnOct, OR = O-n-C8H17
3
4
5
6
13-OcHex, OR = O-c-C6H11
H
7
8
9
H
H
H
H
Ph
OR
O
O
13-O-Chol, OR =
13-O-Preg, OR =
Ph
O
O
H
N
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Ph
HOR, [H+]
O
Et
Ph
Ph
OH
O
S
SR
HSR, [H+]
O
O
+
N
N
N
Ph
Ph
Ph
13-S=OEt
11H2
13-SEt, SR = -C2H5
13-SnHex, SR = -n-C6H13
NHR2, benzene, !,
Soxhlet, 3Å mol sieve
Ph
NR2
O
13-Nmorph, NR2
=
N
O
N
Ph
13-N(Bn)2, NR2 = -N(Bn)2
Scheme 5. Derivatization of porpholactol 11H2 by nucleophilic substitution of the lactol hydroxy group.
This high reactivity of lactol 11H2 with respect to acetal, aminal, and thioacetal formation is of
immediate interest for the potential application of the 2-oxachlorins as photochemotherapeutics. We
previously demonstrated the efficacy of 11H2 when incorporated into a biodegradable nanoparticle for the
photodynamic treatment of a tumor in a mouse model.31 The facile acetalization demonstrated here
suggests that the biodistribution of the hemiacetal may also be modulated by its ability to undergo
derivatization with biomolecules containing alcohol and thiol groups. Such promiscuity may allow
achievement of a biodistribition of the drug it would not have as a single and stable compound. Inversely,
the facile derivatization of the 3-hydroxy-2-oxachlorins suggests the preparation of amphiphilic
(pro)drugs using PEGs, carbohydrates, or similarly suitable moieties. These aspects of the
oxazolochlorins are currently being studied in detail.
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Comparison of Porpholactones and Oxazolochlorins to their Carbaporphyrin Analogues.
Carbaporphyrins are porphyrin analogues containing a carbon atom in place of an inner nitrogen. Pawlicki
and Latos-Grazynski reported the total synthesis of 17, the carbaporphyrin analogue to 3-methoxy-2-
oxachlorin 13-OEt.44,45 This reaction is in contrast to our ‘breaking and mending of porphyrin’ strategy
toward porpholactones 5. Like 13-OEt (see below), 2-oxa-21-carbachlorin 17 possesses a chlorin-like
spectrum (λSoret = 437 nm and four Q-bands with λmax = 672 nm). The synthesis of the free base non-
macrocycle-aromatic 2-oxa-21-carbaporphyrin could not be achieved. Multi-step oxidation of 17 led to
the formation of porphyrnoid 18, the carbaporphyrin analogue to porpholactone 5. The UV-visible
spectrum of 18 is, in similar fashion to its aza-analogue, porphyrin-like with a sharp Soret band and four
Q-bands (λmax = 690 nm). Unlike the azaporphyrins, however, the metallocarbaporphyrin chemistry is
dominated by reactions on the inner carbon.46
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Ph
OH
O
+ 3
O
Ph
N
H
OH
Ph
N
N
CHO
Tol
Ph
H
N
+ 2
16
Tol
1. BF3·Et2O
2. DDQ, EtOH
Ph
Ph
O
H
OEt
O
O
N
N
N
H
H
Tol
Ph
Tol
Ph
H
H
N
N
N
Tol
17
18
Tol
Scheme 6. Synthesis of 2-oxa-21-carbaporphyrin 16, 2-oxa-21-carbachlorin 17, and 2-oxa-3-oxo-21-
carbaporphyrin 18.
Optical Properties of Porpholactones and Oxazolochlorins. Free base porpholactones possess UV-
visible and fluorescence emission spectra that are almost indistinguishable from those of the
corresponding porphyrins (Figure 2). The similarity of the porphyrin and porpholactone spectra, noted
already upon their discovery,3,4 is surprising as the modified pyrrolic moiety has lost its cross-conjugated
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β,β’-double bond. Therefore, porpholactones could have been expected to possess chlorin-like spectra.42
Evidently, however, the electronic effects of the carbonyl double bond mimic the presence of a β,β’-
double bond. On the other hand, porpholactone Zn(II) complexes exhibit metallochlorin-like UV-visible
spectra, though they are slightly hypsochromically shifted when compared to the spectra for
metallochlorin 7aZn. On the basis of iterative extended Hückel calculations, Gouterman and co-workers
categorized porpholactones to lie between porphyrins and chlorins.4
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The reduced porpholactones, 3-hydroxy-2-oxachlorins 11H2 (λmax = 646 nm) and 11Zn, both possess
chlorin-like optical spectra (cf. to the spectra for 7aH2, λmax = 648 nm, and 7aZn). The influence of the
3-hydroxyl functionality on the 2-oxachlorin chromophore is profound. The removal of this group in the
free base chromophore 12H2 results in a 22 nm red-shift (λmax = 668 nm) in the UV-visible spectrum. We
have demonstrated before the distinct blue-shifts caused by OH-substitution of chlorin pyrrolidines.19
Most surprisingly, the removal of the hydroxy group also results in a significant enhancement of the
extinction coefficient of the Qx band relative to its Soret band. Thus, replacement of the CH2CH2 group in
chlorins by a CH2O group has an auxochromic effect, adding to the collection of groups that are known to
substantially modify the chlorin chromophore.43 The computations presented below will offer a
rationalization for this observation.
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Figure 2. Normalized UV-visible (solid traces) and fluorescence spectra (broken traces) of the
compounds indicated (all in CH2Cl2 at ambient temperature). Their extinction coefficients are presented in
the experimental section.
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Theoretical Analysis of the Free Base Optical Spectra Energies and Intensities. The theoretical studies
presented here seek to refine the understanding of the porphyrin-like optical spectra of porpholactones and
the photophysical origins of the unusual intensity and red-shifted transition energy of the Qx band in
2-oxachlorin 12aH2. Because this compound readily oxidizes, we doubted the reliability of the molar
extinction coefficient measurements. Thus, the spectra shown in Fig. 2 are all relative to a normalized
Soret band. This approach is logical, but presents a problem because the SAC-CI and MNDO-PSDCI
calculations predict that the intensity of the Soret band, which is made up of two or more transitions, will
also change with the modifications. To provide a consistent analysis, we integrated the experimental
absorption bands in energy space to provide oscillator strength ratios. The solvent-averaged results allow
a consistent comparison of the calculated and observed values (Table 1).
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Table 1. Ratios of the oscillator strength of the Qx band divided by the oscillator strength of the Soret
band as a function of solvent and comparison to computed ratios.
#
%
$
&
(
(Qx )
"
)104
(QSoret
)
'
"
7aH2
Solvent
1aH2
5aH2
11H2
12H2
Exp. Averagea
SAC-CIb
82
69
230
348
499
0
120
115
303
377
MNDO-PSDCIc
Dipole Moment (D)d
51
21
6
28
117
0.0000
0.0000
5.0056
4.7023
3.5992
0.8262
1.3018
1.2315
1.1781
1.3615
Dipole Moment* (D)e
a
Average of the results obtained in 11 solvents (CHCl3, CH2Cl2, DMSO, n-hexane, acetone, EtOAc,
MeCN, MeOH, THF, pyridine, toluene). For a detailed listing of the solvatochromic properties of 12H2,
see the ESI.
b From Figure 3 (left panel).
c From Figure 3 (right panel).
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d B3LYP/6-31G(d) dipole moments computed without the phenyl rings.
e B3LYP/6-31G(d) dipole moments computed with the phenyl rings.
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The results of the high-accuracy (level two) SAC-CI calculations are shown in Figure 3 (left panel).
These calculations do not include the phenyl groups, and thus we are observing purely those effects
associated with substitutions within the macrocycle. The SAC-CI calculations predict that 12aH2 will
have the most intense Qx band (Table 1). However, the observed intensity ordering (5aH2 < 1aH2 < 7aH2
< 11H2 < 12H2) differs from the SAC-CI predicted intensity ordering (1aH2 < 7aH2 < 5aH2 < 11H2 <
12H2) in that 5aH2 is calculated to have significantly more Qx intensity than is observed. An examination
of the MNDO-PSDCI calculations, which include the phenyl groups, indicates that the origin of the
failure of the SAC-CI calculations on 5aH2 may be associated with the neglect of the phenyl groups.
However, the semiempirical calculations (Fig. 3, right panel) underestimate all of the Qx band intensities,
transferring too much oscillator strength into the Qy bands.
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Figure 3. Level ordering of the low-lying electronic transitions of the chromophores investigated. Each
electronic transition is represented by a rectangle with vertical position corresponding to the transition
energy and height proportional to the oscillator strength. The oscillator strengths for selected transitions
are shown in black directly above or below selected transition markers. The red numbers at bottom
represent the ratio of the Qx oscillator strength divided by the total oscillator strength of the Soret bands
multiplied by 104; cf. to Table 1. Chlorin refers to the parent 2,3-dihydroporphin structure (C20N4H16). Left
panel: Results based on level two SAC-CI molecular orbital theory. These calculations were completed on
modified chromophores in which the phenyl groups were replaced by hydrogens. Right panel: Results
based on MNDO-PSDCI molecular orbital theory. The MNDO-PSDCI calculations were carried out on
chromophores that included the phenyl groups.
The first and most important observation is that, perhaps contrary to intuition, the dipole moments of
the ground state species do not have a significant impact on either the intensities or the red-shifted
character of the Qx bands. The calculated dipole moments, shown in Table 1, correlate with neither the
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oscillator strengths nor the excitation energies of the bands. Rather, the most red shifted and most intense
Qx band observed in 2-oxachlorin 12H2 is observed in a molecule with an intermediate dipole moment of
the group studied here.
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We examined the configurational characteristics of the Qx bands and concluded that the key mechanism
responsible for both the red shift and the enhanced oscillator strength is mixing of the Qx band with the
low-lying transitions in the Soret region. In the C2v symmetry of chlorin, the Qx band and the lowest Soret
band at ~3.4 eV share the same symmetry (B2). However, the charge shift upon excitation into the Qx
band decreases the dipole moment of the molecule, a property characteristic of a covalent state (see ESI).
In contrast, the lowest Soret band (S3) is an “ionic” state, and despite the highly polar environment of the
chlorin, these two states do not share configurational space. The insertion of an oxygen atom in place of
one of the methylene moieties in the chlorin macrocycle breaks up the symmetry, and has a significant
impact on the excitation induced charge shifts (see ESI). In particular, all of the excited states are now
ionic, and this mixing increases the ground state dipole moment of the molecule. The lowest Qx band
mixes with the S3 Soret transition with an approximately 28% configurational overlap, which transfers
oscillator strength from S3 into Qx. This mixing is visually apparent by reference to Figure 2. Note that
the oscillator strength of S3 decreases by an amount comparable to the increase in the oscillator strength
of Qx. Furthermore, the configurational mixing “pushes” these two states apart energetically. Thus,
electrostatically induced configurational mixing between S1(Qx) and S3(Soret) is responsible for both the
increased oscillator strength and the increased red shift of the Qx band.
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The MNDO-PSDCI calculations provide insight into the impact of the phenyl groups on the relative
properties of the Qx bands. It is noted that while these semiempirical calculations underestimate the
intensities of all the Qx bands of the chlorins, these calculations do indicate that the Qx band of
oxazolochlorin 12H2 is significantly more intense than the others, as is observed. The phenyl group near
the oxygen atom in this compound rotates slightly to form a weak hydrogen bond between the oxygen
atom and the nearby phenyl hydrogen atom (shown in the ESI). Upon excitation, this interaction promotes
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a charge shift that is attributed to an enhanced mixing of Qx and the S3 state. Thus in the case of 12H2, the
phenyl groups increase both the red-shift and oscillator strength of Qx by enhancing the mechanisms
responsible for the analogous effects in the compound without phenyl rings.
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Conclusions
We detailed an efficient synthesis of meso-tetraarylporpholactones from meso-tetraarylporphyrins in
two steps using a number of aryl substituents and free base and metallochlorins. We demonstrated this
reaction previously for the synthesis of a 21,23-dithiaporpholactone17 and two porpholactone N-oxide
isomers.18 Thus, this methodology can be regarded to be general. In so doing, we have further expanded
the synthetic methodologies of converting a porphyrin to pyrrole-modified porphyrins along our ‘breaking
and mending of porphyrins’ strategy.
A number of porpholactones (tetraphenylporpholactones 5aH2 and 5aZn, diphenylporpholactone 15-II-
Zn) were structurally characterized, displaying their structural relationship to the corresponding
porphyrins but also suggest the presence of a steric interaction between the oxazolidone moiety with the
flanking phenyl group. The similarity of the optical properties of porphyrins and porpholactones highlight
their close electronic relationship.
Replacing a porphyrinoid β,β’-bond by a lactone results in a porphyrin-like optical spectrum for the free
base chromophores but more metallochlorin-like properties for the metalloporpholactones. A stepwise
reduction of the carbonyl group of 5aH to an alcohol in porpholactol 11H2 establishes a chlorin-like
spectrum in the free base and zinc(II) complexes. Further reduction of the hemiacetal moiety forms the
novel oxazolochlorin chromophore 12H2. Compared to porpholactol 11H2 or 2,3-dihydroxychlorin 7aH2,
it features a significantly red-shift chlorin-like spectrum with an increased extinction coefficient of the Qx
band. This effect could be traced back by computational analysis to an electrostatically induced
configurational mixing between S1(Qx) and S3(Soret) that is made possible by the desymmetrization of
the chromophore upon replacement of the pyrrolidine moiety in a regular chlorin by an oxazole moiety.
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X-ray crystal structure analyses of chromophores in all oxidation states showed their planarity, thus
providing evidence for the absence of conformational effects in the modulation of their optical spectra.
The presented examples highlight the subtleties that control the structure-electronic properties
relationships of porphyrinoids.
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The simple syntheses of porpholactones and 2-oxachlorins, their facile derivatization to stable chlorin
derivatives potentially bearing many kinds of side chains, and their optical properties are likely to
encourage the further study and application of these intriguing chromophores.
Experimental Section
Theoretical. Calculations were carried out by using semiempirical MNDO-PSDCI molecular orbital
theory4730 as well as SAC-CI theory.48 The MNDO-PSDCI calculations used the AM1 Hamiltonian. The
configuration interaction included all 64 singles and 2,080 doubles generated from the eight highest
energy filled and eight lowest energy un-filled π-orbitals. Calculations were carried out with and without
phenyl groups for comparative purposes. The SAC-CI calculations were carried out using a full double
zeta D95 basis set,49 which has yielded excellent results for large polyatomic chromophores.50 Level two
integral selection generated a CI basis sets of roughly ~9,500 singles and ~600,000 doubles. The SAC-CI
calculations were carried out on modified structures where hydrogens replaced all of the phenyl groups.
All calculations were carried out on structures minimized by using B3LYP/6-31G(d) density functional
theory.
X-Ray Single Crystal Diffractometry: X-ray crystallographic analysis: Single crystals of 5aH2, 5aZn,
12H2, 13-OMe, and 15-II-Zn were coated in either Paratone®-N (Exxon) or Fomblin® oil, mounted on a
pin and placed a goniometer head under a stream of nitrogen cooled to 100 K. The data were collected on
a either a Bruker APEX (5aH2, 5aZn, 12H2) or APEX2 (13-OMe, and 15-II-Zn) CCD diffractometer
with Mo source Kα radiation (λ = 0.71073). The frames were integrated with the Bruker SAINT software
package using a narrow-frame algorithm. Data were corrected for absorption effects using the multi-scan
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method (SADABS) and the structure was solved and refined using the Bruker SHELXTL Software
Package until the final anisotropic full-matrix, least squares refinement of F2 converged. Data collection
and structural parameters for the structure elucidations of 5aH2, 5aZn, 12H2, 13-OMe, and 15-II-Zn can
be found in the ESI.
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Materials and Instrumentation: meso-Tetraarylporphyrins 1H2 were synthesized according to the
method of Adler.51 The metal complexes 1aZn, 1aNi, 1aPd, and 1aPt were prepared from free base
meso-tetraphenylporphyrin 1aH2 as described in the literature.52
Flash column chromatography was performed manually in glass columns or on an automated flash
chromatography system, on normal-phase silica (solvents used are indicated; isocratic eluation modes).
meso-Tetrakis(4-i-propyl)-cis-2,3-dihydroxychlorin 7bH2. Prepared in 31% overall yield (270 mg,
2.93 × 10-4 mol) from meso-tetrakis(4-i-propyl)phenylporphyrin (1bH2) (1.00 g, 1.12 × 10-3 mol)
according to a published general procedure.16 Rf (silica-CH2Cl2) = 0.22, (silica-CH2Cl2/1% MeOH) 0.35;
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1H NMR (400 MHz, CDCl3, δ): 8.67 (d, J= 4.8 Hz, 2H), 8.50 (s, 2H), 8.33 (d, J = 4.8 Hz, 2H), 8.07–
8.02 (m, 6H), 7.85 (d, 7.36 Hz, 2H), 7.61–7.54 (m, 8H), 6.39 (s, 2H), 3.24–3.17 (m, 6H), 1.52–1.48 (m,
24H), –1.74 (s, 2H, exchangeable with D2O) ppm; UV-visible (CHCl2) λmax (log ε) 418 (5.18), 522 (4.20),
548 (4.06) 594 (3.75), 644 (4.40) nm; HR-MS (ESI+, cone voltage = 30 V, 100% CH3CN, TOF) m/e
calcd for C56H57N4O2 (MH+), 817.4482, found 817.4502.
meso-Tetrakis(4-trifluoromethyl)-cis-2,3-dihydroxychlorin 7fH2. Prepared in 26% overall yield
(270 mg, 2.93 × 10-4 mol) from meso-tetrakis(4-trifluoromethyl)phenylporphyrin (1fH2) (1.00 g, 1.12 ×
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10-3 mol) according to a published general procedure.16 Rf (silica-CH2Cl2) = 0.28; H NMR (400 MHz,
CDCl3, δ): 8.62 (d, 3J = 4.0 Hz, 2H), 8.43 (s, 2H), 8.30 (d, 3J = 4.0 Hz, 2H), 8.27–8.20 (m, 6H), 8.03–7.93
(m, 10H), 6.27 (s, 2H), 3.10 (s, 1H, exchangeable with D2O), –1.90 (s, 2H, exchangeable with D2O) ppm;
UV-visible (CHCl2) λmax (log ε) 408 (5.18), 515 (4.12), 542 (4.07) 593 (3.75), 645 (4.39) nm; HR-MS
(ESI+, cone voltage = 30 V, 100% CH3CN, TOF) m/e calcd for C48H28F12N4O2 (MH+) 921.2089, found
921.2128.
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meso-Tetrakis(4-methoxy)-cis-2,3-dihydroxychlorin 7eH2.22 Prepared in 21% overall yield (220 mg,
2.86 × 10-4 mol) from meso-tetrakis(4-methoxy)phenylporphyrin (1eH2) (1.00 g, 1.36 × 10-3 mol)
according to a general procedure.16 Rf (silica-CH2Cl2/5% MeOH) = 0.49; 1H NMR (400 MHz, CDCl3, δ):
8.66 (d, 3J = 4.0 Hz, 1H), 8.50 (s, 1H), 8.33 (d, 3J = 4.0 Hz, 1H), 8.06 (br d, 8.0 Hz 3H), 7.84 (d, 8.0 Hz,
1H), 7.22 (d, 8.0 Hz, 4H), 6.37 (s, 1H), 4.05 (two overlapping s, 6H), 3.21 (s, 1H, exchangeable with
D2O), –1.76 (s, 1H, exchangeable with D2O) ppm; UV-visible (CHCl2) λmax (log ε) 418 (5.27), 522 (4.16),
5.51 (4.24), 594 (3.92), 645 (4.38) nm; HR-MS (ESI+, cone voltage = 30 V, 100% CH3CN, TOF) m/e
calcd for C48H40N4O6 (MH+) 769.3021, found 769.2991.
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General procedure for the preparation of porpholactones 5 by oxidative diol cleavage of 2,3-
dihydroxychlorins 7. To a stirring solution of 7 (0.32 × 10-4 mol, for 7aH2 206 mg) in 25 mL THF was
added 18-C-6 (28 mg, 10-4 mol, 0.33 eq). KMnO4 (251 mg, 1.58 mmol, ~5 equiv) was added to the
solution, and the mixture was allowed to react for 12 h at ambient temperature, and the reaction monitored
by TLC. If needed, additional oxidant was added after 12 h until the starting material was exhausted. The
solution was then filtered through a short plug of silica gel or Celite, and the filter cake washed with
CH2Cl2 until the filtrate was colorless. The combined filtrates were evaporated to dryness by rotary
evaporation. The product was purified by column chromatography (silica/CHCl3), followed by
crystallization.
Alternatively, dihydroxy chlorins 7 can be, under the same reaction conditions, reacted with 2-5 equiv
of cetyltrimethylammonium permanganate in CH2Cl2, followed by the workup described above, also
providing excellent yields of 5.
meso-Tetrakisphenyl-3-oxo-2-oxaporphyrin (5aH2). Prepared as crystalline material in 75% isolated
yield (150 mg) according to the general procedure from 7aH2. Recrystallization from CHCl3/EtOH. Our
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IR, UV-vis, LR-MS, H NMR, and analytical data are essentially identical with those reported by
Crossley.3,53 Supplemented by C, optical, and HR MS data, they are included here for the purpose of
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better comparison with the data reported for the reduction products below. Rf (silica-CCl4/CH2Cl2 1:1) =
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0.50; 1H NMR (400 MHz, CDCl3, δ): 8.80 (dd, 3J = 5.2, 4J = 1.5 Hz, 1H), 8.77 (dd, 3J = 4.8, 4J = 1.5 Hz,
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1H), 8.70 (dd, J = 4.8, J = 1.5 Hz, 1H), 8.60 (d, J = 4.6 Hz, 1H), 8.58 (dd, J = 5.0, J = 1.7 Hz, 1H)
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1H, exchangeable with D2O), –2.05 (s, 1H, exchangeable with D2O); C NMR (100 MHz, CDCl3, δ):
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167.7, 157.1, 154.6, 154.2, 141.6, 141.5, 141.4, 139.4, 138.7, 138.4, 137.6, 137.0, 135.3, 134.5, 134.4,
134.3, 133.8, 132.7, 130.2, 130.1, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.2, 127.1,
126.3, 125.7, 121.7, 119.4, 102.9 ppm; UV-vis (CHCl3) λmax (log ε) 420 (5.56), 522 (4.15), 558 (4.16),
588 (3.95), 640 (3.66); UV-visible (TFA/CHCl3) λmax 430, 588 (sh), 614; HR-MS (FAB, 3-NBA,
quadrupole) m/e calc’d for C43H28N4O2: 632.2212, found 632.2148; Anal. calc’d for C43H28N4O2: C, 81.63:
H, 4.46: N, 8.85%. Found: C, 81.44; H, 4.44; N, 8.80%.
[meso-Tetrakisphenyl-3-oxo-2-oxaporphyrinato]Zn(II) (5aZn). Prepared either according to the
general procedure by oxidation of 7Zn in 85% isolated yield or, in quantitative yields, by Zn(II)-insertion
into 5H2 using 2 h reflux in CHCl3/EtOH containing 3 eq Zn(II)(OAc)2·2H2O, followed by slow solvent
exchange CHCl3 to EtOH on the rotary evaporator. The purple course crystals were filtered and air-dried.
Rf (silica-CH2Cl2) = 0.19 or (silica-ethyl acetate/hexane 3:1) = 0.82; 1H NMR (400 MHz, CDCl3, δ): 8.75
(d, 3J = 4.5 Hz, 1H), 8.68, 8.67 (two overlapping d, 3J = 4.5 Hz, 2H), 8.63 (d, 3J = 4.5 Hz, 1H), 8.56 (d, 3J
= 4.5 Hz, 1H), 8.51 (d, 3J = 4.5 Hz, 1H), 8.11 (d, J = 7.8, 2.0 Hz, 4H), 8.06 (dd, J = 7.8, 2.0 Hz, 2H), 7.93
(dd, J = 7.8, 2.0 Hz, 2H), 7.657.77 (m, 12H); 13C NMR (75 MHz, CDCl3, δ): 173.5, 154.1, 143.4, 142.1,
142.0, 139.0, 138.0, 134.3, 134.0, 133.8, 132.4, 132.3, 132.2, 132.0, 130.9, 130.7, 130.6, 129.5, 128.8,
127.9, 127.8, 127.7, 127.6, 127.5, 126.7, 126.6; UV-visible (CH2Cl2) λmax (log ε) 402 (sh), 422 (5.53), 520
(3.54), 558 (4.07), 602 (4.44); LR-MS (EI, 250°C) m/e 694 (30.9, M+), 638 (7.3), 561 (17.4), 483 (3.5),
28 (100); HR-MS (DART+, orifice voltage = 30 V, 100% CH3CN, TOF) m/e calc’d for C43H27N4O264Zn
(MH+): 695.1425, found 695.1429.
[meso-Tetraphenyl-3-oxo-2-oxaporphyrinato]Ni(II) (5aNi). Prepared in 55% yield (10-4 mol scale)
from 7aNi according to the general procedure. Rf (silica-CH2Cl2) = 0.74; 1H NMR (400 MHz, CDCl3/10%
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MeOD, δ): 8.55 (d, J = 4.0 Hz, 1H), 8.51–8.47 (two overlapping d, J = 4.0 Hz, 2H), 8.45–8.41 (two
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visible (CHCl2) λmax (log ε) 415 (5.24), 543 (3.96), 586 (4.49) nm; HR-MS (ESI+, cone voltage = 30 V,
100% CH3CN, TOF) m/e calcd for C43H26N458NiO2 (M+): 688.1409, found: 688.1426.
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meso-Tetrakis(4-i-propylphenyl)-3-oxo-2-oxaporphyrin (5bH2). Prepared in 77% yield (13 mg) from
7bH2 (2.0 × 10-5 mol, 17 mg) according to the general procedure. Rf (silica-CH2Cl2) = 0.90; 1H NMR (400
MHz, CDCl3, δ): 8.83, 8.81 (two overlapping dd, 3J = 4.5, 4J = 1.5 Hz , 2H), 8.74 (dd, 3J = 4.6, 4J = 1.3 Hz
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1H), 8.63 (d, J = 4.5 Hz, 1H) 8.61, 8.59 (dd, J = 4.5, 4J = 1.5 Hz, 1H), 8.56 (d, J = 4.6 Hz, 1H), 8.07–
8.02 (m, 6H), 7.90 (d, 8.0 Hz, 2H), 7.60–7.58 (m, 8H), 3.28–3.19 (m, 4H), 1.54–1.50 (m, 24H), –1.62 (s,
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1H, exchangeable with D2O), –2.00 (s, 1H, exchangeable with D2O) ppm; C NMR (100 MHz, CDCl3,
δ): 167.6, 156.9, 154.5, 154.1, 148.7, 148.59, 148.57, 148.54, 141.2, 139.3, 138.8, 138.7, 138.6, 136.9,
135.5, 135.0, 134.8, 134.7, 134.4, 134.29, 134.26, 133.5, 132.6, 129.9, 129.8, 127.7, 127.5, 126.0, 125.9,
125.6, 125.5, 125.0, 124.9, 121.5, 119.3, 102.7, 34.11, 34.06, 24.25, 24.19 ppm; UV-visible (CHCl2) λmax
(log ε) 421 (5.46), 523 (4.01), 562 (4.09), 590 (3.81), 642 (3.10) nm; HR-MS (ESI+, cone voltage = 30 V,
100% CH3CN, TOF) m/e calcd for C55H52N4O2, (MH+) 801.4169, found 801.4149.
meso-Tetrakis(4-t-butylphenyl)-3-oxo-2-oxaporphyrin (5cH2). Prepared in 73% yield (32 mg) from
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7cH2 (5.0 × 10-5 mol, 43 mg) according to the general procedure. Rf (silica-CH2Cl2) = 0.89; H NMR
(400 MHz, CDCl3, δ): 8.83 (s, 2H), 8.74 (d, 3J = 4.0 Hz, 1H), 8.63–8.59 (two overlapping d, 3J = 4.0 Hz,
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4H), 1.60, 1.59, 1.57 (3 s, 36H), –1.62 (s, 1H, exchangeable with D2O), –1.99 (s, 1H, exchangeable with
D2O) ppm. 13C NMR (100 MHz, CDCl3, δ): 167.6, 156.9, 154.3, 154.0, 151.0, 150.9, 150.8, 150.7, 141.2,
139.3, 138.5, 138.4, 138.3, 136.9, 135.1, 135.0, 134.4, 134.19, 134.09, 134.04, 133.4, 132.3, 129.8, 129.7,
127.7, 127.5, 126.0, 125.4, 124.7, 124.4, 123.9, 123.7, 121.4, 119.3, 102.7, 34.92, 34.91, 34.88, 31.66,
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