Post-Synthetic Modification of Hangman Porphyrins Synthesized on the Gram Scale

Article abstract of DOI:10.1002/cssc.201402242

We report a multi-gram scale synthesis of methyl 6-formyl-4-dibenzofurancarboxylate and its subsequent use in the gram scale synthesis of a dibenzofuran-functionalized hangman porphyrin containing a pendant carboxylic acid (HPD-CO₂H). HPD-CO₂H can be isolated as a free carboxylic acid in high purity with minimal purification. Post-synthetic modification of HPD-CO₂H allows for the introduction of any desired pendant group in good yields, resulting in a practical amount of hangman porphyrin ligand with an easily customizable second coordination sphere. The cobalt complexes of these hangman porphyrins are shown to be active proton reduction electrocatalysts.

Full text of DOI:10.1002/cssc.201402242

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DOI: 10.1002/cssc.201402242
Post-Synthetic Modification of Hangman Porphyrins
Synthesized on the Gram Scale
Daniel J. Graham, Shao-Liang Zheng, and Daniel G. Nocera*[a]
We report a multi-gram scale synthesis of methyl 6-formyl-4-di-
benzofurancarboxylate and its subsequent use in the gram
scale synthesis of a dibenzofuran-functionalized hangman por-
phyrin containing a pendant carboxylic acid (HPD-CO2H). HPD-
CO2H can be isolated as a free carboxylic acid in high purity
with minimal purification. Post-synthetic modification of HPD-
CO2H allows for the introduction of any desired pendant
group in good yields, resulting in a practical amount of hang-
man porphyrin ligand with an easily customizable second co-
ordination sphere. The cobalt complexes of these hangman
porphyrins are shown to be active proton reduction electro-
catalysts.
ing acid/base functionalities above a single transition metal
complex has been largely unexplored and limited to hanging
carboxylic acids.[4,32] Building on our experience with hangman
ligands containing carboxylic acids, we chose to pursue a modi-
fication strategy to post-synthetically attach hanging groups
via carboxamide formation. Herein, we report the high yielding
synthesis of greater-than-one-gram of hanging porphyrin di-
benzofuran with a pendant carboxylic acid (HPD-CO2H) using
a modified Lindsey method[33] and 3,4,5-trimethoxy-benzalde-
hyde (TMB) as the second aldehyde. The origin of this unusual-
ly high yield for a porphyrin compound is presumably due to
similar electronic properties of TMB and dibenzofuran alde-
hyde. HPD-CO2H can be cleanly isolated with minimal purifica-
tion and post-synthetically modified through carboxamide for-
mation with any primary amine, allowing for rapid generation
of a library of hangman porphyrins with systematic variation of
proton donor properties and/or steric hindrance. We further
show that cobalt complexes of HPD are competent proton re-
duction electrocatalysts.
Ligand design for the purpose of controlling the secondary co-
ordination sphere of a metal site is a popular strategy to en-
hance catalytic activity. The effect of placing a pendant acid/
base moiety in the second coordination sphere of metallocy-
cles on ligand binding,[1–3] as well as on the catalytic transfor-
mations of peroxide dismutation,[4–12] H2 generation,[13,14] H2O
oxidation,[15,16] and O2 reduction,[16–22] has been an intense
topic of study. The concept of using the secondary coordina-
tion sphere to influence activity of redox reactions involving
protons has subsequently been generalized to a variety of
metal centers and secondary coordination spheres.[23] The strat-
egy has been especially important for promoting the hydrogen
evolution reaction (HER), which involves coupling the reduc-
tion of a metal center to proton transfer.[24–29] In our hangman
approach, xanthene has been a preferred scaffold for the as-
sembly of macrocycles such as porphyrins or salens with
a pendant acid/base group, which has primarily been a carbox-
ylic acid. We have sought to expand the hangman methodolo-
gy to include more sterically imposing pendant groups that
not only assist in proton transfer, but also shield the metal
center from the bulk solution and effectively create a substrate
binding pocket. In order to accommodate larger hanging
groups, we have turned our attention to the dibenzofuran
scaffold. The dibenzofuran precursor that is needed for macro-
cyclic construction can be synthesized on the gram scale from
inexpensive starting materials. Whereas this dibenzofuran
spacer has been employed in the construction of Pacman com-
plexes,[30,31] the use of dibenzofuran as a platform for append-
1. Scaffold synthesis: the synthesis of HPD-CO2H requires an
asymmetric dibenzofuran containing an aldehyde functionality
and a pendant methyl ester, which can be subsequently hydro-
lyzed after porphyrin formation to yield the free carboxylic
acid. The synthesis of methyl 6-formyl-dibenzofuran-4-carbox-
ylate (4) is carried out in 4 steps on the multigram scale. First,
dibenzofuran was selectively deprotonated at the 4 and 6 posi-
tions using the combination of n-BuLi and TMEDA in refluxing
hexanes. The resulting dilithio salt was quenched with CO2 at
À788C, yielding 4,6-dibenzofuran dicarboxylic acid (1) after
acidic workup. Impure 1 was often used directly in the next
step after removal of excess water in vacuo. 1 was converted
to dimethyl-4,6-dibenzofuran dicarboxylate (2) by acid-cata-
lyzed esterification in refluxing methanol (MeOH) with trimeth-
yl orthoformate as a dehydrating agent (Scheme 1). 2 is easily
isolated by precipitation upon addition of excess water fol-
lowed by filtration and drying in vacuo. Column chromatogra-
phy yields analytically pure 2. However, it was found that
impure 2 could be used in the following step after sufficient
drying in vacuo.
[a] D. J. Graham, Dr. S.-L. Zheng, Dr. D. G. Nocera
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford St, Cambridge, MA 02138 (USA)
E-mail: dnocera@fas.harvard.edu
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201402242.
Scheme 1. Synthesis of 2 from dibenzofuran.
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Following published methods,[34] statistical reduction of 2
was accomplished by treatment with NaBH4 in a refluxing THF/
MeOH solution to yield 6-(hydroxy-methyl)dibenzofuran-4-car-
boxylate methyl ester (3). Subsequent oxidation of 3 with
TEMPO and bis(acetoxy)iodosylbenzene (BAIB) in DCM gave
the desired porphyrin precursor (4) in 38% overall yield start-
ing from dibenzofuran (Scheme 2).
Scheme 2. Synthesis of hangman porphyrin precursor 4 by the statistical re-
duction and subsequent oxidation of 2.
In an attempt to synthesize the desired asymmetric alde-
hyde in three steps, 2 was treated with one equivalent of
DIBAL-H. Curiously, regardless of solvent, reaction time, or tem-
perature, only starting material was recovered. An additional
equivalent of DIBAL-H resulted in a 1:1 mixture of 2 and fully
reduced dialcohol, 4,6-di(hydroxymethyl)dibenzofuran (5)
(Scheme 3).
Scheme 4. Formation for the porphyrin from pyrrole, TMB, and 4.
agent concentrations resulted in more non-porphyrinic by-
products, but still gave remarkably high yields of porphyrin.
Notably, this method gives relatively poor yields of hangman
porphyrin when other aldehydes, such as pentafluorobenzalde-
hyde (10%), mesitylaldehyde (12%), or 2,4,6-trimethoxybenzal-
dehyde (7%), were used in the same ratios in conjunction with
4.
HPD-CO2Me is difficult to separate from other porphyrinic
byproducts due to similar elution properties, but hangman
porphyrin could be isolated cleanly by carrying the entire por-
phyrin mixture directly through to the next step and hydrolyz-
ing the hanging methyl ester (Scheme 4). After filtering off
a majority of the pyrrolic byproducts, microwave-assisted basic
hydrolysis[37] converted HPD-CO2Me to the corresponding
HPD-CO2H, which is easily separated from unreacted HPD-
CO2Me and A4 porphyrin on a silica column. Starting with
a 2.1 mm solution of 4 in 1.5 L of CHCl3, HPD-CO2H was isolat-
ed in 33% over two steps on a gram scale. The yield of HPD-
CO2H increased to 41% if performed on a smaller scale in
560 mL of CHCl3, keeping all reagent concentrations the same.
In addition to HPD-CO2H, 1.64 g (30% yield with respect to
total available TMB) of A4 was isolated and identified by
1H NMR. Even though it is a byproduct, the yield of A4 is simi-
lar to its synthesis by published methods.[38,39]
Scheme 3. Attempted selective reduction of 2 by DIBAL-H.
2. Porphyrin construction: porphyrins are notoriously diffi-
cult to synthesize on a large scale, especially those featuring
multiple meso-substituents. Whereas all previous reported syn-
theses of hanging dibenzofuran ligands have employed Pd-cat-
alyzed cross coupling, we decided to attempt statistical por-
phyrin formation with 4 because the products of Pd cross-cou-
pling reactions retain minute amounts of Pd that are capable
of driving the HER catalytically.[35] Our most common means of
hangman porphyrin synthesis employs the Lindsey method in
a highly dilute solution containing excess pyrrole and non-
hangman aldehyde in order to maximize the yield of hangman
porphyrin.[36,37] Following this published strategy, treatment of
a 0.53 mm solution of 4, containing an overall 1:15:16 ratio of
4/TMB/pyrrole, with BF3·OEt2 resulted in an unusually high
combined yield of tetrakis(3,4,5-trimethoxyphenyl)porphyrin
(A4) and hanging porphyrin dibenzofuran methyl ester (A3B,
HPD-CO2Me) with few other byproducts. Given the surprising
ability of TMB and 4 to form porphyrin rings in a respectably
selective fashion, statistical synthesis was attempted by sub-
jecting a 2.1 mm solution of 4 in CHCl3, with a 1:7:8 ratio of 4/
TMB/pyrrole, to the Lindsey method (Scheme 4). The higher re-
3. Hanging group attachment: the presence of 3,4,5-trime-
thoxyphenyl meso-substituents on HPD-CO2H precludes the
use of thionyl chloride in carboxamide formation.[40,41] Instead,
a combination of p-toluenesulfonyl chloride (TsCl) and N,N-di-
methylaminopyridine (DMAP) was employed to prepare the
acyl transfer reagent. Treatment of HPD-CO2H with 2–5 equiva-
lents of TsCl and 4–10 equivalents of DMAP followed by addi-
tion of excess aryl amine afforded the functionalized hangman
porphyrins, which were easily purified and isolated in good
yield (Scheme 5).
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the CÀC(O)NHR bond and maintain the desired second coordi-
nation sphere.
4. Cobalt insertion and HER electrocatalysis: the CoII com-
plexes are synthesized using published microwave-assisted
metallation procedures.[37] The Co complex HPDCo-2AP dis-
plays waves in the cyclic voltammogram (CV) that correspond
to CoIII/II, CoII/I, and CoI/“0” electron transfer events. The CV of the
HPDCo-2AP changes dramatically upon the titration of
HBF4·OEt2 into a CH3CN solution of 0.1m tetraethylammonium
p-toluenesulfonate ([TEA]+[TsO]À), which generates tosic acid
(TsOH) in situ. A catalytic wave appears at the CoII/I reduction
(Figure 2). This behavior differs significantly from that of other
Scheme 5. Post-synthetic modification of hanging group with isolated yields
for each hangman porphyrin derivative.
Crystals suitable for X-ray diffraction studies were grown
from slow evaporation of an acetonitrile (CH3CN) solution of
HPD-Ph. The porphyrin crystallized as a dimer and displayed
the expected connectivity (Figure 1). The center of the hanging
phenyl ring is positioned 4.474(2) ꢁ above the mean porphyrin
plane. The porphyrin ring is slightly saddled, which has the
effect of tilting the hangman scaffold inward and decreasing
the distance between the hanging group and the porphyrin
plane. The presence of an intramolecular NH···O hydrogen
bond is apparent between the carboxamide NH group and the
central dibenzofuran O atom, with an N–O distance of
2.791(3) ꢁ and NÀHÀO bond angle of 141.90(1)8. This hydro-
gen bond may provide an anchor to prevent rotation around
Figure 2. Cyclic voltammograms of a 0.5 mm solution of HPDCo-2AP in
CH3CN (0.1m [TEA+][TsOÀ]) with 0 mm (c), 1 mm (c), 2 mm (c),
5 mm (c), 10 mm. (c), 15 mm (c), and 20 mm (c) of added
HBF4·OEt2. Scan rates are 50 mVsÀ1
.
Co-hangman porphyrins with a pendant carboxylic acid in the
presence of TsOH,[13] in which a catalytic wave is observed at
potentials significantly negative of the CoII/I reduction wave,
suggesting that CoIIIH, generated from protonation of CoI,
must be reduced to CoIIH before H2 evolution occurs. The
hanging pyridine is a significantly stronger proton donor than
the xanthene carboxylic acid, and may be capable of protonat-
ing CoIIIH directly. Further studies concerning the differences in
proton reduction rates with different hanging groups are un-
derway.
In summary, HPD-hangman porphyrins with 3,4,5-trimethox-
yphenyl meso-substituents can be synthesized from inexpen-
sive starting materials that are either commercially available or
easily made on a multigram scale; and they can be isolated on
a gram scale with minimal purification. Using these hangman
porphyrins as ligands for transition metals allows one to con-
trol the nature of the secondary coordination sphere. Subse-
quent functionalization of HPD-CO2H allows for the installation
of any pendant group with tunable steric, electronic, and/or
proton donating properties. Cobalt complexes of these new
hangman porphyrins are capable of reducing protons electro-
catalytically. Studies on the mechanism for H2 evolution and
on the use of other metalloporphyrins derived from hanging
porphyrin dibenzofuran are currently underway.
Figure 1. Solid state molecular structure of HPD-Ph with 50% ellipsoids. All
carbon-bound hydrogens are removed for clarity.
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DJG is thankful for the financial support offered by the NSF GRFP
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Keywords: electrocatalysis · gram scale · hangman porphyrin ·
hydrogen · porphyrin
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Published online on && &&, 0000
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D. J. Graham, S.-L. Zheng, D. G. Nocera*
&& – &&
Post-Synthetic Modification of
Hangman Porphyrins Synthesized on
the Gram Scale
Not a noose-ance anymore! Hangman
porphyrins can now be synthesized on
the gram scale from inexpensive start-
ing materials. Using these hangman
porphyrins as ligands for transition
metals allows control of the nature of
the secondary coordination sphere.
Post-synthetic modification is used to
introduce a wide range of hanging
groups with tailored characteristics that
facilitate proton delivery during electro-
catalysis.
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