Oxazolochlorins 21. most efficient access to meso-tetraphenyl- And meso-tetrakis(pentafluorophenyl)porpholactones, and their zinc(II) and platinum(II) complexes

Article abstract of DOI:10.3390/molecules25184351

meso-Phenyl- and meso-pentafluorophenyl-porpholactones, their metal complexes, as well as porphyrinoids directly derived from them are useful in a number of technical and biomedical applications, and more uses are expected to be discovered. About a dozen

Full text of DOI:10.3390/molecules25184351

molecules
Article
Oxazolochlorins 21. Most Efficient
Access to meso-Tetraphenyl- and
meso-Tetrakis(pentafluorophenyl)porpholactones,
and Their Zinc(II) and Platinum(II) Complexes
Damaris Thuita, Dinusha Damunupola and Christian Brückner *
Department of Chemistry, University of Connecticut, Unit 3060, Storrs, CT 06269–3060, USA;
damaris.thuita@uconn.edu (D.T.); dinudamunupola@uconn.edu (D.D.)
* Correspondence: c.bruckner@uconn.edu; Tel.: +1-(860)-486-2743
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: M. Graça P. M. S. Neves
Received: 14 August 2020; Accepted: 16 September 2020; Published: 22 September 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: meso-Phenyl- and meso-pentafluorophenyl-porpholactones, their metal complexes, as
well as porphyrinoids directly derived from them are useful in a number of technical and
biomedical applications, and more uses are expected to be discovered. About a dozen competing
and complementary pathways toward their synthesis were reported. The suitability of the methods
changes with the meso-aryl group and whether the free base or metal derivatives are sought.
These circumstances make it hard for anyone outside of the field of synthetic porphyrin chemistry
to ascertain which pathway is the best to produce which specific derivative. We report here on
what we experimentally evaluated to be the most efficient pathways to generate the six key
compounds from the commercially available porphyrins, meso-tetraphenylporphyrin (TPP) and
meso-tetrakis(pentafluorophenyl)porphyrin (TFPP): free base meso-tetraphenylporpholactone (TPL)
and meso-tetrakis(pentafluorophenyl)porpholactone (TFPL), and their platinum(II) and zinc(II)
complexes TPLPt, TFPLPt, TPLZn, and TFPLZn, respectively. Detailed procedures are provided to
make these intriguing molecules more readily available for their further study.
Keywords: porphyrin; porphyrinoids; porpholactone; oxidation
1. Introduction
Porpholactones, members of the family of so-called pyrrole-modified porphyrins [1],
are porphyrinoids in which a ß,ß’-bond of the parent porphyrin was replaced by a lactone moiety. From
the perspective of the tetrapyrrolic structure of porphyrins, a pyrrolic building block was replaced by
an oxazolidone (Scheme 1).
Scheme 1. Generalized formation of meso-arylporpholactones from meso-arylporphyrins.
Molecules 2020, 25, 4351; doi:10.3390/molecules25184351
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The historically first porpholactone, meso-tetraphenylporpholactone (TPL) was derived from
meso-tetraphenylporphyrin (TPP) [ ]. While several phenyl- and substituted phenyl-derivatives were
reported [ ], the by far most popular derivative is the meso-tetrakis(pentafluorophenyl)porpholactone
2
3,4
(TFPL) and its metal complexes (TFPLM) [
1,5,6]. This is because of their relative ease of synthesis
in one step from TFPP using a number of different methodologies (see below Scheme 2) and the
multiple possibilities to derivatize the C6F5-groups by means of nucleophilic aromatic substitution
reactions to, for example, render them water-soluble [
carbaporphyrins [ ], thiaporphyrins [10 11], octaalkylporphyrins [12], or subporphyrins [13] is known
but much more rare and the utility of these compounds has not yet been shown.
6–8]. The presence of a ß,ß’-lactone moiety in
9
,
Scheme 2.
Select literature-known reaction conditions toward the formation of meso-aryl
(metallo)porpholactones. TPP = meso-tetraphenylporphyrin; TPPM = [meso-tetraphenylporphyrinato]
metal complex; TFPP = meso-tetrakis (pentafluorophenyl)porphyrin; TFPPM = [meso-tetrakis
(pentafluorophenyl)porphyrinato] metal complex; TPL = meso-tetraphenylporpholactone; TPPM =
[meso-tetraphenylkporpholactonato] metal complex; TFPL = meso-tetrakis(pentafluorophenyl)
porpholactone; TFPLM = [meso-tetrakis(pentafluorophenyl)porpholactonato] metal complex.
Upon the replacement of one or two ß,ß’-bond(s) of the parent porphyrin by lactone moieties,
the electronic structure of the chromophore is altered, sometimes in profound ways, even though the
UV-vis spectra of free base TPP and TPL are surprisingly similar to each other [
4
]. The electronic
16]. On account
influence of the lactone moieties on the chromophore was studied in some detail [ 14–
4–
6,
of only a minor steric interaction between the carbonyl oxygen and the o-hydrogen/fluorine atoms
on a neighboring meso-aryl group, the introduction of one (or even two) lactone moieties alters the
idealized planar conformation of the parent porphyrins only in subtle ways [4,14,16–18].
Like their porphyrin congeners [19], both TPL and TFPL are competent ligands for a wide range
of metals, forming the metal complexes TPLM and TFPLM, respectively (with M = MgII, NiII, MnIII,

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FeIII, ZnII, YIII, AgII, PdII, PtII, YbIII) [
4–
6
,20
–
23]. The metal ions may already be present in the
metalloporphyrin/chlorin starting materials or are inserted later into the free base macrocycle.
meso-Arylporpholactones and their metal complexes have found utility as, for instance,
olefin epoxidation [24], hydroformylation [25], nitrogen transfer [23], sulfoxidation [26],
or electrochemical hydrogen evolution reaction catalysts [27
functionalizations [29]. Other porpholactones found uses as chlorophyll models [14] or as bioinorganic
models for intermediates in the catalytic cycles of heme-based peroxidases, catalases, and oxidases [ ].
Porpholactones are better lanthanide sensitizers than porphyrins [21] and served as bioimaging [21] or
phototheranostic agents [30], oxygen-sensing dyes in pressure-sensitive paints [31 33], optical cyanide
sensors [ 34], or high-pH sensors [35 36], including as ratiometric dye suitable for the full-field
,28], or as photocatalysts for oxidative C-H
3
–
7
,
,
optical mapping of the pH of concrete surfaces [36]. TFPL-based photosensitizers also exhibit higher
lipoprotein binding affinity, cellular uptake, and intracellular localization selectivity when compared
to the parent porphyrins [37].
Multiple distinct pathways of converting (metallo)porphyrins to (metallo)porpholactones were
described in nearly two dozen individual papers. Some were specifically developed to provide
porpholactones, others became the source of porpholactones by serendipity (Scheme 2) [1,6]. For all
methods, the exact mechanisms of the formation of porpholactones are not known. It appears, however,
that (metallo)porpholactones are generally a thermodynamic sink in the oxidative degradation pathways
of many ß-substituted (metallo)-porphyrins/chlorins. Simple one-step reactions that generate a
porpholactone directly from a porphyrin are generally burdened by the need to isolate the porpholactone
from unreacted porphyrin (of similar Rf value as the porpholactone) and among several other
(over)oxidation products [
or were tested for their applicability to varying aryl groups. On the other hand, the oxidation of
several ß-substituted (metallo)-porphyrins ( ) and -chlorins ( ) converted them to porpholactones
in more rational and sometimes even selective fashion [ ], facilitating the isolation of the product
5,38]. In addition, not all conditions are applicable to all meso-arylporphyrins,
1
,
3
2
3,4
of relative low polarity from the starting materials of (much) higher polarity. Alas, some of the
reactions are inefficient or the starting materials require a multi-step synthesis from the corresponding
porphyrins [
2–
4,
39]. Except for the MnO4–-oxidations of diol chlorin
2, a reaction specifically developed
for the synthesis of porpholactones [
4], none of the reactions were shown to possess some generality
with respect to the meso-aryl group or a central metal ion present.
As the number of inquiries from non-porphyrin chemist practitioners we received over the years
clearly highlighted to us, the many known methods and pathways toward porpholactones present a
hard to navigate maze for the non-specialist. A decision as to which option is the most expedient, safe,
simple, or economical is not readily possible. There appears to be no commercial source for any of
the porpholactones.
Over the course of the past decade [40], we developed and optimized our own procedures
or evaluated numerous syntheses published by others toward the synthesis of free base TPL/TFPL,
and their zinc(II) and platinum(II) complexes. In this contribution, we like to delineate in detail the
most efficient paths toward TPL/TPLZn/TPLPt and TFPL/TFPLZn/TFPLPt we are aware of, with the
aim of providing the non-specialist access to these intriguing and versatile materials. The procedures
spelled out (see Supporting Information) were derived from published methods developed by us [4],
or the research group of Zhang [41], and tested multiple times in our laboratories. The detailed
procedures incorporate hitherto unpublished practical details.
2. Results and Discussion
Since the most efficient pathways toward the meso-phenyl- and meso-pentafluorophenyl-substituted
porpholactones vary, we will discuss the syntheses of these two families separately.

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2.1. The Most Efficient Pathway toward TFPL/TFPLZn/TFPLPt
TFPP is readily synthesized [42] or is commercially available from a variety of supply houses,
as are its metallated derivatives TFPPM (for M = ZnII or PtII) [43
44]. Their better solubility renders
,
the fluorinated derivatives to be a great platform for many modification reactions, including their
one-step conversion to the corresponding (metallo)porpholactones TFPL/TFPLM. We found the
RuCl3/Oxone®-mediated oxidation pathway, as described by Zhang and co-workers [41], to be the
most efficient pathway to generate free base TFPL as well as TFPLMs (for M = ZnII or PtII) by oxidation
of the corresponding porphyrin metal complexes TFPPM (for M = ZnII or PtII). The reaction was
described to be more suitable for substrates bearing electron-withdrawing meso-substituents [41].
The ruthenium-catalyzed oxidation is a one-step, one pot process in a biphasic mixture of
ClCH2CH2Cl (1,2-dichloroethane) and H2O/NaOH in which the oxidant mixture RuCl3/bipy/Oxone®
is heated with the starting (metallo)porphyrin (dissolved in the organic phase) under reflux
conditions [41]. Depending on the reactivity of the substrate, the reaction allows a convenient
variation of the oxidant:substrate stoichiometry, as well as reaction times. The reaction is robust to
minor deviations in the reaction conditions. Even though several products may be formed that require
their chromatographic separation, under the optimized conditions, the reaction is simple, reasonably
fast, clean, and comparatively high-yielding.
Under the standard ruthenium-catalyzed oxidation conditions reported by Zhang and co-workers
(0.5 eq RuCl3, 0.5 eq bipyridine, 5 eq Oxone®, 5 eq NaOH, 5 h reaction time), about 60–75% TFPP
converted, yielding multiple products. The major product is chromatographically isolated free base
TFPL (~30% isolated yield at a 500 mg of TFPP scale, Rf = 0.52 (silica/CH2Cl2)), along with a mixture of
dilactones (in 10–15% yield, Rf = 0.31 (silica/CH2Cl2)) but that are readily separated, as is the unreacted
TFPP (Rf = 0.76 (silica/CH2Cl2)). Increasing the oxidant stoichiometry in combination with extended
refluxing times led to full conversion of the porphyrin and an increase of the yield of TFPL to up to
45% (at a 200 mg of TFPP scale), with the remainder made up by the dilactone mixture. See Supporting
Information for a detailed procedure and reproduction of the key spectra of all products.
Metallation of TFPP generally increases its susceptibility towards the Ru-mediated oxidation [41];
accordingly, the formation of the corresponding TFPLM is faster and higher yielding in comparison to
the formation of their free base congener [41]. Thus, the oxidation of the metalloporphyrins TFPPZn and
TFPPPt to obtain the corresponding metalloporpholactones TFPLZn/Pt (Scheme 3) is much preferred
over the insertion of zinc(II)/platinum(II) into free base TFPL, although the latter is also an option [
4,45].
Scheme 3. The synthesis of meso-tetrakis(pentafluorophenyl)porpholactone (TFPL) and its zinc(II)
(TFPLZn) and platinum(II) (TFPLPt) complexes.
Under the standard oxidation conditions (1 eq TFPPM, 0.5 eq RuCl3, 5 eq Oxone®, 0.5 eq bipyridine,
5 eq NaOH, 5 h reaction time), TFPPZn provided TFPLZn in 35% yield (at a scale of 500 mg of TFPPZn).
The yield can be increased to 50–60% when the initial concentrations of TFPPZn and RuCl3 are doubled
along with a corresponding increase of oxidant (10 eq Oxone®, 10 eq NaOH) and using extended
reaction times (up to 72 h). In both cases, a mixture of dilactone isomers is observed to be the major
byproduct (in yields of 15–20% under the standard oxidation conditions). TFPLPt was produced in

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~50% yield from TFPPPt under the standard conditions (at a scale of 100 mg of TFPPPt) and, again,
along with the dilactone mixture as the primary byproduct (~10–15%). Increase of the ratio of oxidant
to 15 eq and reaction times up to 48 h increases the yield of TFPLPt substantially (up to 75%), along with
an increased yield of the dilactone mixture (20%). For both metalloporpholactones, preparative plates
(500
µ
m silica gel, 20
×
20 cm plates) can be conveniently used for the isolation of the product in
small scale reactions (40–50 mg). Larger scale reactions were purified using column chromatography.
The products are identified based on their diagnostic UV-vis, 1H NMR, and IR spectroscopy or mass
spectrometry data (see ESI).
–
None of the other direct oxidation methods (using MnO4
[17]; Ag(I) [5], or Au(III) [46]) could
compete in terms of yields, scalability, and ease of separation of the desired products with the
RuCl3/Oxone®/base methodology [41]. While a two-step method analogous to that described below
for the syntheses of the nonfluorinated derivatives TPL/TPLM works well for the synthesis of
TFPL/TFPLM [
4,17], it is unnecessarily arduous and only worth pursuing when selectively dilactone
derivatives are desired [17].
2.2. The Most Efficient Pathway toward TPL/TPLZn/TPLPt
Porphyrin TPP is readily synthesized in multi-gram scales [47–49] and, modestly priced [43].
Its zinc(II) complex TPPZn is readily formed [19]. While the corresponding platinum(II) complexes
TPPPt can also be formed [45 50], its low solubility in most solvents make it nearly intractable and
,
unsuitable as a starting materials for the preparation of TPLPt using any of the available methods.
Therefore, TPLPt needs to be prepared by the platinum(II) insertion into the free base porpholactone
TPL using either conventional thermal [50] or microwave-assisted [45] methodologies.
The one-step RuCl3-mediated oxidation of the comparably electron-rich TPP is less efficient
(isolated yields of 10–30% of TPL at a 200 mg scale) compared to the oxidation of the fluorinated
analogue TFPP [41], thus requiring larger stoichiometric ratios of the oxidant as well as longer reaction
times (up to one week, or more). In our hands, the isolation of the porpholactone at any larger scale
from its side products proved also to be non-trivial. Neither TPP nor TPPZn are susceptible to the
MnO4–- [17], or Ag(I)-mediated [
5] oxidation protocols. The Au(III)-mediated oxidation of the silver(II)
complex of TPP forms the free base TPL in 23% yield [46], but this route is also not truly competitive
(and the oxidant costly). Thus, access to the porpholactone TPL is best achieved along a multi-step
processes, with access to TPLZn/Pt by means of zinc(II) and platinum(II) insertions into the free base
TPL, respectively.
Among the possible multi-step processes toward TPL (Scheme 1), one process stands out
as particularly suitable for its simplicity and high yields: We have reported in detail [51
both the OsO4-mediated cis-vic-dihydroxylation, followed by a diol oxidation of the intermediate
dihydroxychlorin [ 17 53 54]. However, there a number of variabilities in these processes:
,52],
4, , ,
The intermediate osmate ester can be isolated and oxidized, or the osmate ester is reduced to a
–
diol and is then oxidized, with a number of possible oxidants for either step (MnO4 with the counter
cations cetyltrimethyl ammonium (CTAP) or [18-C-6]·K+ [4,53]; CrO3 [17,54]).
The most simple, scalable and highest yielding process we find is the osmylation of TPP (performed
in up to a 5 g scales), the isolation of osmate ester
H2S, to form chlorin diol 51], and finally a CrO3-mediated oxidation of the diol (performed in up
to 300 mg scales) (Scheme 4) [17 54]. The overall yield of 45% of TPL over all three steps from TPP
4, followed by its reductive cleavage using gaseous
2
[
,
is good (even without considering that ~20% of TPP is recovered after the first step), the reaction is
scalable, straight-forward, and well-controlled.
In detail, the synthesis of TPL involves first, an OsO4-mediated dihydroxylation step to yield
the intermediate osmate ester
H2S gas. Isolated polar product
over 30 min under ambient conditions; this produced the readily isolable non-polar bright pink
compound TPL (in 35–40% overall isolated yield). The use of a 20 20 cm, 500 m silica gel preparative
4
that is isolated and subsequently reduced to diol
2 by a purge of
2
is then oxidized to TPL using CrO3 in the presence of pyridine
×
µ

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chromatography plate for scales up to 50 mg diol is convenient; above this column chromatography is
advisable. We observed that the oxidation shows best results when run in small batches of 250–300 mg
of 2
; the reaction appears to be retarded at scales of 500 mg, or more. Diagnostic UV-vis, 1H NMR,
and IR spectroscopy or mass spectrometry data can be used to unequivocally identify the product TPL
and its metal complexes. See Supporting Information for a detailed procedure and a reproduction of
the key spectra of all products and intermediates.
Scheme 4. The most efficient synthesis of meso-tetraphenylporpholactone (TPL) and its zinc(II) (TPLZn)
and platinum(II) (TPLPt) complexes.
Metal insertions into free base TPL prepare the desired metal complexes [4]. See Supporting
Information for a detailed procedure and a reproduction of the key spectra. While the zinc(II) complex
TPLZn can, in principle, also be prepared from the soluble porphyrin zinc complex TPPZn, the isolation
of the intermediate chlorin is easier for the free base (the metallochlorin is significantly more polar and
‘streaks’ during chromatographic separation). Also, the diol oxidation of the chlorin diol zinc complex
is characterized by lower yields that the corresponding free base chlorin diol oxidation.
The biggest drawback of this multi-step method toward TPL/TPLM is the use of the toxic reagents
OsO4, H2S, and CrO3. The risk of working with OsO4 can be minimized by scaling the osmylation
reactions such that entire 250 mg, 500 mg, or 1 g ampules of OsO4 can be used; they can be opened
(fume hoods, hand and eye protection needed) and immediately be drowned (cap and body) in the
reaction mixture that is then stoppered and left to react. Before the reactions are worked up, the glass
vials are retrieved. The use of H2S and CrO3 can be circumvented by oxidation of the osmate ester
4
with CTAP (or KMnO4/18-C-6) [53]. However, the yields for these reactions are slightly lower (25–30%),
particularly at larger (> 250 mg diol osmate ester) scales. The reaction is hard to control and often leads
to ‘overoxidation’. Practical difficulties in the isolation of the product resulting from the formation
of the hard-to-remove sludges the CTAP side products form also contribute to the lower isolated
yields at larger scales. Lastly, using the osmate ester
4
as substrate, the fate of the osmium is unclear
–
upon MnO4 -oxidation [35,52]. Thus, given the risks involved with re-generating OsO4 unwittingly,
these oxidations require also great care, mitigating some of the advantages of avoiding CrO3.
3. Materials and Methods
3.1. Materials
All solvents and reagents (Sigma-Aldrich, St. Louis, MO, USA and Acros, Fair Lawn, NJ, USA)
were used as received. TFPP [42] was either synthesized according to the literature procedure or
obtained commercially [43,
44]. TFPPZn [42] and TFPPPt [20] were synthesized by metal insertion

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into the free base according to literature procedures. TPP was synthesized according to a literature
procedure [47], and it is also commercially readily available [43,44].
All solvents were reagent-grade, or better, and were used as received. The CHCl3 used was
EtOH-stabilized (amylene-stabilized CHCl3, for example, is unsuitable for the osmylations).
Aluminum-backed, silica gel 60, 250-
µm thickness analytical plates were used for analytical TLC;
Either 20 20 cm, glass-backed, silica gel 60, 500
×
µ
m thickness preparative TLC plates or standard
grade, 60 Å, 32–63 µm flash column silica gel were used for the preparative chromatography.
Detailed procedures with spectroscopic data and reproduction of the key spectra of the products
and intermediates (were present) are provided in the ESI.
3.2. Two-Step Procedure for Synthesis of meso-Tetraphenyl-2-Oxa-3-Oxoporphyrin (TPL) by OsO4-Mediated
Dihydroxylation, Followed by CrO3 Oxidation
3.2.1. Dihydroxylation of TPP; Synthesis of meso-Tetraphenyl-2,3-cis-dihydroxychlorin 2
To a 500 mL round-bottom flask equipped with a stir bar, meso-tetraphenylporphyrin (TPP) (2.20 g,
3.58 mmol) was dissolved in a mixture of CHCl3 (270 mL, EtOH-stabilized) and freshly distilled
pyridine (30 mL). A glass ampoule of 1.0 g of OsO4 (1.0 g, 3.93 mmol, ~1.1 equiv.) was opened and
immediately submerged (cap and body) into the mixture. The flask was then stoppered, shielded from
light with aluminum foil, and stirred at ambient temperature (20–24 ◦C) The progress of the reaction
was monitored by occasional TLC. Once no further progress was noted (after about 4 days), the solvent
was removed on a rotary evaporator as best as possible. The crude osmate ester product was then
dissolved in a solution of 10% MeOH/CHCl3 (~250 mL). The osmate ester was then reductively cleaved
by purging with gaseous H2S for 5 min (Note 2); the mixture was stirred for an additional 30 min
before the majority of the excess H2S was purged from the solution by a stream of nitrogen gas through
the solution. Following the addition of further MeOH (20 mL), the precipitated black OsS was filtered
off through a short plug of Celite®. The filtrate was evaporated to dryness by a stream of N2 or rotary
evaporation. The resulting residue was dissolved in a minimal amount of CHCl3 and loaded onto a
silica gel column (25
(250 mg, 11% recovery). CH2Cl2/1.5% MeOH then eluted diol chlorin
MeOH/CH2Cl2 mixture provided product as a bright purple crystalline material (1.00 g, 1.40 mmol,
×
7 cm) and eluted with CH2Cl2. The first fraction was starting material TPP
2. Slow evaporation from a
2
49% yield). Rf (silica−CH2Cl2/1.5% MeOH) = 0.68.
All reaction steps, including the solvent removal involving the H2S-exposed solutions,
were performed in a fume hood following usual laboratory safety practices (gloves, eye protection
and lab coats). Caution: Note the hazard and risk of using OsO4 (acute oral and inhalation toxin,
skin irritant, serious danger to eye damage). Further, note the hazard and risk of using H2S (fatal if
inhaled, extended exposure reduces the ability to smell the gas; flammable). A fume hood is essential.
Trap all excess H2S (bleach traps, for example).
3.2.2. Synthesis of meso-Tetraphenyl-2-oxa-3-oxoporphyrin (TPL) via CrO3 Oxidation of Diol 2
In a 25 mL round-bottom flask equipped with a stir bar and two carbon pellets,
meso-tetraphenyl-2,3-cis-dihydroxychlorin
2 (100 mg, 0.154 mmol) was dissolved in pyridine (5 mL).
Chromium trioxide CrO3 ( 10 equiv., 154 mg, 1.54 mmol) was added to the solution. The round-bottom
∼
flask was shielded from light with aluminum foil and stirred at ambient temperature. The disappearance
of the starting material and the appearance of the product were monitored by TLC. Once no further
progress of the reaction was detectable (after
was transferred into a 125 mL separatory funnel and washed with water (3
phase was separated and filtered through a short plug of diatomaceous earth (Celite®) and dried over
anhyd. Na2SO4. The drying agent was removed by gravity filtration and the filtrate was evaporated to
dryness by rotary evaporation. A gentle stream of N2 passed through the crude material for several
h ensured that the crude material was thoroughly dried. The crude material was dissolved in a few
∼
30 min), CH2Cl2 (25 mL) was added and the mixture
25 mL). The organic
×

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mL CH2Cl2 coated onto silica. The material was then dry-loaded onto a flash column (~6 × 25 cm
)
silica–CH2Cl2) and chromatographed to provide TPL in 40–60% yield (60 mg) as a pinkish red solid.
Rf (silica–CH2Cl2) = 0.67.
All reaction steps described below, except for the solvent removal, were performed in a fume hood
following usual laboratory safety practices (gloves, eye protection and lab coats). Caution: CrO3 is a
strongly oxidizing solid, toxic if swallowed, causes severe skin burns, is mutagenic, and a reproductive
toxin. Eye protection and gloves needed when handling this chemical.
3.3. Preparation of Metalloporpholactone TPLZn via Zinc Insertion into Free Base TPL
A 250 mL round-bottom flask was equipped with a stir bar, heating mantle, and a reflux condenser.
The flask was charged with porpholactone TPL (123 mg, 1.94 mmol) and Zn(OAc)2 2H2O (123 mg,
·
0.193 mmol, 3 equiv.) dissolved in CHCl3/MeOH (8:1, 80 mL). The reaction mixture was heated to
reflux for ~2 h. Upon completion of reaction as observed by TLC, the reaction mixture was cooled to
room temperature and filtered through Celite®. The filtrate was concentrated, the concentrate was
loaded onto the silica gel column, and purified by short column chromatography (silica, CH2Cl2) to
produce TPLZn as a purple-colored film. Recrystallization by dissolution in a few mL of CH2Cl2,
addition of ~50% MeOH, and slow removal of the CH2Cl2 on a rotary evaporator (at ambient T)
precipitated TPLZn; it was retrieved by filtration and air-dried to provide TPLZn as a bright purple
crystalline solid in 97% yield (130 mg, 0.143 mmol). Rf (silica–CH2Cl2) = 0.44.
All steps, except for the solvent removal, were performed in a fume hood following usual
laboratory safety practices (gloves, eye protection and lab coats).
3.4. Preparation of Metalloporpholactone TPLPt via Platinum Insertion into Free Base TPL
A 50 mL round-bottom flask was equipped with a stir bar, heating mantle, a reflux condenser
and a N2 inlet. TPL (65.0 mg, 0.086 mmol) was dissolved in benzonitrile PhCN (5 mL) and added to a
refluxing solution of benzonitrile PhCN (20 mL) and PtCl2 (61 mg, 0.344 mmol, 4 equiv.). The mixture
was heated to reflux for 3 h. When the starting material was consumed (reaction monitored by
TLC), the reaction mixture was allowed to cool and was evaporated to dryness by rotary evaporation.
The resulting mixture was dissolved in CH2Cl2 (2–5 mL), loaded as solution onto a flash column
(silica-CH2Cl2) and chromatographed. TPLPt was isolated in 71% (50 mg) yield as a magenta powder.
Rf (silica-CH2Cl2) = 0.17.
All steps, except for the solvent removal, were performed in a fume hood following usual
laboratory safety practices (gloves, eye protection and lab coats).
3.5. One-Step Synthesis of meso-Tetrakis(pentafluorophenyl)-2-oxa-3-oxoporphyrin TFPL by
RuCl3/Oxone®-Mediated Oxidation. General Procedure
In a 750 mL round-bottom (or a two-neck, round-bottom) flask equipped with a stir bar and reflux
condenser, TFPP (0.8 g, 0.8 mmol, 1 equiv.) and RuCl3 (85 mg, 0.4 mmol, 0.5 equiv.) were dissolved in
1,2-dichloroethane (ClCH2CH2Cl, 250 mL). A solution containing 2,20-bipyridine (65 mg, 0.4 mmol,
0.5 equiv.) in ClCH2CH2Cl (7 mL) and water (250 mL) were added. A condenser was attached to one
of the necks and the solution was heated to reflux. A mixture of Oxone® (7.4 g, 12 mmol, 15 equiv.)
and NaOH (480 mg, 12 mmol, 15 equiv.) in water (15 mL) was added periodically in five equal portions
over the course of 5 h to the refluxing solution. After completion of the addition, the reaction mixture
was refluxed overnight. The mixture was allowed to cool to room temperature, quenched with a
saturated aqueous solution of Na2S2O3 (2.0 g in 5 mL of water). The reaction mixture was stirred,
allowed to stand for 30 min, and transferred to a 750 mL separatory funnel. The (bottom) organic layer
was separated, and the aqueous layer was extracted twice using CH2Cl2 (2
organic fractions were washed with a saturated aqueous NaCl solution (2
layer was dried with anhydrous Na2SO4 (30 min) and the drying agent was removed by gravity
filtering. The filtrate was reduced to dryness using rotary evaporation (in a 500 mL round-bottom
×
150 mL). The combined
150 mL). The organic
×

Molecules 2020, 25, 4351
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flask). The residue was dissolved in CH2Cl2 (2–5 mL), loaded as a solution onto a packed column
(silica, 5
×
60 cm, with a fritted disk, eluent: CH2Cl2/hexanes = 2:1) and separated to obtain the product
TFPL as a purple solid upon solvent removal in 30% yield (240 mg, 0.24 mmol). Rf (silica–CH2Cl2/20%
hexane) = 0.68.
All steps, except for the solvent removal, were performed in a fume hood following usual
laboratory safety practices (gloves, eye protection and lab coats). CAUTION: 1,2-Dichloroethane is
harmful if swallowed, causes skin and eye irritation, toxic if inhaled, and is considered as a potential
carcinogen. Flammable with a flash point of 13 ◦C.
3.6. Synthesis of [meso-Tetrakis(pentafluorophenyl)-2-oxa-3-oxoporphyrinato]zinc(II) (TFPLZn)
Prepared in 35% yield (189 mg) as a bright purple powder according to the general procedure for
the synthesis of TFPL synthesis using TFPPZn (0.52 g, 0.5 mmol, 1 equiv.) and RuCl3 (53 mg, 0.25 mmol,
0.5 equiv.) in ClCH2CH2Cl (150 mL) and water (150 mL), respectively in a 500 mL round-bottom flask
equipped with a stir bar was mixed with a solution of 2,20-bipyridine (40 mg, 0.25 mmol, 0.5 equiv.) in
ClCH2CH2Cl (5 mL). A mixture of Oxone® (3.1 g, 5 mmol, 10 equiv.) and NaOH (290 mg, 5 mmol,
10 equiv.) in water (15 mL) was added periodically over 5 h in equal portions. TLC control. Workup as
per general procedure. Rf (silica–CH2Cl2/20% hexanes) = 0.48.
3.7. Synthesis of [meso-Tetrakis(pentafluorophenyl)-2-oxa-3-oxoporphyrinato]platinum(II) (TFPLPt)
Prepared in 50% yield (191 mg) as a reddish powder according to the general procedure described
for the synthesis of TFPL synthesis using TFPPPt (100 mg, 0.16 mmol, 1 equiv.) and RuCl3 (16.6 mg,
0.08 mmol, 0.5 equiv.) in ClCH2CH2Cl (50 mL) and water (50 mL) in a 250 mL round bottom flask,
mixed with a solution of 2,20-bipyridine (12.5 mg, 0.08 mmol, 0.5 equiv.) in ClCH2CH2Cl (1.5 mL).
A mixture of Oxone® (243.5 mg, 1.6 mmol, 10 equiv.) and NaOH (64.0 mg, 1.6 mmol, 10 equiv.) in
water (5 mL) was added in five portions over 5 h while the solution was refluxed for 8 h. Work up
and isolation of product were carried out according to the general procedure. Rf (silica–CH2Cl2/20%
hexanes) = 0.52.
4. Conclusions
The most efficient pathways toward the most popular free base porpholactones, TPL and
TFPL, and their zinc(II) and platinum(II) complexes TPLZn/TPLPt and TFPLZn/TFPLPt, respectively,
are described. The pathways differ and are dependent on the substrate reactivity and solubility:
The RuCl3/Oxone® mediated oxidation of TFPP/TFPPM is the preferred pathway toward the
meso-pentafluorophenylporpholactones TFPL/TFPLM. The metalloporphyrins are suitable starting
materials for the direct formation of metalloporpholactones. However, a multi-step process is best for
the non-fluorinated derivatives TPL and subsequent metal insertion into the free base porpholactone
provides access to the metal complexes TPLZn/TPLPt. A number of variations for the multi-step
process are available, depending on the comfort level of the researchers working with H2S and/or CrO3.
The preparation of multi-100 mg quantities of all (metallo)porpholactones in acceptable yields can be
achieved in predictable ways from commercially available materials, but chromatographic separations
are required in all cases.
The broader significance of the work lies in the provision of clearly navigable pathways toward
the porpholactones that were selected by our own laboratory experience from among the many
complementary and competing pathways described in the literature. While the porpholactones
described are of broad utility, access to the free base porpholactones also enables entry to a number
of other metalloporpholactones. Moreover, closely related porphyrins of utility can be derived,
like the thionolactones used as hypochlorite sensors [18], the porpholactone reduction products
porpholactols [
as chlorolactones and chlorolactams [59
even if alternative synthetic pathways for the latter porphyrinoid were developed that circumvent
4,
55–
57] useful as photosensitizers [58] or hydrogen evolution catalysts [28], as well
,
60], porpholactams [59 60], and imidazoloporphyrins [60],
,

Molecules 2020, 25, 4351
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the intermediate porpholactone [61]. The method described also allow direct access to the
meso-pentafluorophenyl-substituted porphodilactone isomers of broad utility [17], though longer but
more rational syntheses might be desirable when more than 10−5 mol quantities are desired of either
the fluorinated or non-fluorinated series [17,62].
We hope this work will encourage more researchers outside the synthetic porphyrin community
to prepare and study these intriguing porphyrinoids.
Supplementary Materials: Figure S1: Image of 1 g ampule of OsO4, Figure S2: Image of H2S reaction set-up,
Figure S3: 1H NMR (400 MHz, CDCl3) spectrum of meso-tetraphenyl-2,3-cis-dihydroxychlorin
2
, Figure S4: UV-vis
spectrum (CH2Cl2) of meso-tetraphenyl-2,3-cis-dihydroxychlorin
2, Figure S5: Image of the reaction flask, Figure
S6: Image of the silica gel flash column chromatographic separation of the reaction mixture, Figure S7: 1H NMR
(400 MHz, CDCl3) spectrum of TPL, Figure S8: UV-vis spectrum (CH2Cl2) of TPL, Figure S9: 1H NMR (400 MHz,
CDCl3) spectrum of TPLZn, Figure S10: UV-vis spectrum (CH2Cl2) of TPLZn, Figure S11: 1H NMR (400 MHz,
CDCl3) spectrum of TPLPt, Figure S12: UV-vis spectrum (CH2Cl2) of TPLPt, Figure S13: Reaction setup, Figure
S14: Separation funnel setup, Figure S15: 1H NMR (400 MHz, CDCl3) spectrum of TFPL, Figure S16: 19F NMR
(376 MHz, CDCl3) of TFPL, Figure S17: UV-vis spectrum (CH2Cl2) of TFPL, Figure S18: Representative TLC
(CH2Cl2/25% hexanes) of the reaction mixture (RM) in comparison to the starting materials (SM) and product
TFPLZn, Figure S19: 1H NMR (400 MHz, CDCl3) of TFPLZn, Figure S20: 19F NMR (376 MHz, CDCl3) of TFPLZn,
Figure S21: UV-vis spectrum (CH2Cl2) of TFPLZn, Figure S22: 1H NMR (400 MHz, CDCl3) of TFPLPt, Figure S23:
19F NMR (376 MHz, CDCl3) of TFPLPt, Figure S24: UV-vis spectrum (CH2Cl2) of TFPLPt.
Author Contributions: Conceptualization, project administration, funding acquisition, and writing—review and
editing, C.B. Data curation, experimentation, validation, and writing—original draft preparation, D.T. and D.D.
All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the U.S. National Science Foundation (NSF) through grant CHE-1800361
(to C.B.).
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
Abbreviations
AcOH
AgOAc
bipy
acetic acid
silver acetate
2,20-bipyridine
18-C-6
CTAP
DMF
MCPBA
PhCN
py
18-crown-6 crown ether
cetyltrimethylammonium permanganate
dimethyl formamide
m-chloroperoxybenzoic acid
benzonitrile
pyridine
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Sample Availability: Samples of all porpholactones described are available from the authors.
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