Polymer-supported synthesis of mono-substituted porphyrins

Article abstract of DOI:10.1016/j.tetlet.2005.07.131

Anchoring of substituted benzaldehydes to soluble and insoluble polymers allows for the synthesis of mono-substituted tetraarylporphyrins without the production of di-, tri-, and tetra-substituted porphyrin side products. The exclusion of the aforemention

Full text of DOI:10.1016/j.tetlet.2005.07.131

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6737–6740
Polymer-supported synthesis of mono-substituted porphyrins
Qifei Yang, Kristina K. Streb and Babak Borhan*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 1 June 2005;revised 16 July 2005;accepted 25 July 2005
Abstract—Anchoring of substituted benzaldehydes to soluble and insoluble polymers allows for the synthesis of mono-substituted
tetraarylporphyrins without the production of di-, tri-, and tetra-substituted porphyrin side products. The exclusion of the afore-
mentioned side products during the synthesis of mono-substituted tetraarylporphyrin acids greatly reduced the complexity during
purification of the product.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Porphyrins have received a great deal of attention as
receptors for chiral recognition due to several unique
features.1 Their planar structures provide a well-defined
binding pocket that is accentuated by substitutions on
the ring. There are many sites that can be derivatized
such as the meso and b-positions, the central metal,
and the inner nitrogen atoms. They are highly chromo-
phoric and ideal for detecting subtle changes in their
close environment such as binding of chiral ligands.
These intermolecular interactions can be easily followed
by UV–vis, CD, fluorescence, NMR, and resonance
Raman.1 Our own interest in the use of porphyrins as
host systems stems from their ability to report the chiral-
ity of bound guests in alkyl connected bis-metallopor-
phyrins based on exciton coupled circular dichroic
spectroscopy.2–7 The synthesis of these hosts depends
heavily on procuring mono-substituted porphyrins
efficiently. Herein, we describe the selective synthesis
of mono-substituted porphyrins on insoluble and solu-
ble polymers.
benzaldehyde in a 4:3:1 ratio. This leads to the synthesis
of the desired mono-substituted porphyrin along with a
mixture of tetraphenylporphyrin, and di-, tri-, and tetra-
substituted compounds. Not only can the chromato-
graphic separation of these compounds be tedious and
time consuming, but also, depending on the substituted
benzaldehyde utilized in the reaction, wasting of this
compound by synthesizing undesired porphyrins can
be synthetically limiting.
We have modified the synthesis of mono-substituted
porphyrins by using insoluble and soluble polymers.
The method of utilizing insoluble support for the syn-
thesis of mono-substituted porphyrins was first devel-
oped by Leznoff and Svirskaya.13 There are several
advantages in synthesizing mono-substituted porphyrins
on polymers. First, it is easy to separate the polymer-
supported species from the small molecules present in
the reaction medium by simple filtration, which in turn
allows for the use of excess soluble starting material to
gain higher yields. Second, the size of the polymer ren-
ders the resin-bound species inaccessible to each other
and, therefore, cross reactions are avoided. This advan-
tage excludes the formation of di-, tri-, and tetra-substi-
tuted porphyrins. Finally, the use of polymers in the
synthesis of mono-substituted porphyrins eases the puri-
fication of the desired product.
The synthesis of structurally complex porphyrins has
seen tremendous progress in the last 30 years,8–11 and
as such the synthesis of mono-substituted porphyrins
can be achieved by utilizing many of the methods that
have been developed.12 However, the most common
and direct methodology to synthesize these mono-
substituted porphyrins is to condense a mixture of pyr-
role, benzaldehyde, and the appropriately substituted
In the strategy presented here, the substituted aromatic
aldehyde that will eventually become the mono-substi-
tuted portion of the final porphyrin is anchored onto a
polymeric backbone. This allows for the construction
of the porphyrin on the polymeric support with pyrrole
and an aldehyde in solution. In this manner, free mono-
substituted aldehyde is not utilized and thus di-, tri-, and
Keywords: Porphyrins;Soluble polymers;Cross-linked polymers;
Mono-substituted tetraarylporphyrins.
*
Corresponding author. Tel.: +1 517 3559715x138;fax: +1 517
3531793;e-mail: babak@chemistry.msu.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.131

6738
Q. Yang et al. / Tetrahedron Letters 46 (2005) 6737–6740
tetra-substituted porphyrins are not synthesized. As
illustrated in Scheme 1, 4-carboxybenzaldehyde was at-
tached to a 2% cross-linked divinylbenzene/polystyrene
beads containing 1 mmol/equiv of benzyl chloride (1)
by reported procedures.14 The functionalized polymer
support with the bound aldehyde 2 was used to synthe-
size the porphyrin. Addition of pyrrole and benzalde-
hyde to the polymer in refluxing propionic acid
followed by DDQ oxidation yielded the mono-substi-
tuted product 3 on the resin and only tetraphenylporph-
yrin in the solution phase. Since benzaldehyde and
pyrrole are inexpensive reagents, the sacrifice in making
tetraphenylporphyrin in solution is well compensated by
the fact that only the mono-substituted porphyrin is syn-
thesized on the polymer. After washing the unbound
reagents and products from the resin with CH2Cl2
(Soxhlet extraction), cleavage of the covalently attached
porphyrin from the beads with NaOH led to the isola-
tion of the desired compound 4 in good purity and 6%
overall yield. The yield is comparable to solution phase
synthesis of 4 in refluxing propionic acid, however, the
crude isolate is not complicated with mixtures of mul-
ti-substituted porphyrins, and thus the purification
proved to be straightforward from the polymer beads.
geneous solution chemistry (high reactivity, lack of dif-
fusion phenomena, and ease of analysis) with those of
solid phase methods (use of excess reagents and easy iso-
lation and purification of products). Non-cross-linked
polystyrene polymers are soluble in THF, CH2Cl2,
CHCl3, and ethyl acetate even at low temperatures,
and are insoluble in water and methanol. Consequently,
after the homogeneous reaction of supported intermedi-
ates, the polymer and its uniquely bound product can be
easily separated from excess reactants and byproducts
by treating with cold methanol, in which the soluble
polymer precipitates as a solid polymer, and the soluble
reagents and byproducts are filtered away. Because the
polymer is soluble in CHCl3, NMR analysis of all inter-
mediates can be accomplished easily.
Non-cross-linked chloromethylate polystyrene (NCPS,
7) was prepared as reported by Chen and Janda by the
copolymerization of styrene (5) with 3 mol% of 4-(chlo-
romethyl) styrene (6) in the presence of 0.06 mol% 2,20-
azobis(isobutyronitrile) (AIBN) in benzene at 70 ꢁC for
40 h.16 The MWavg of 60,000 and a PDI of 2.14 were
measured by GPC for the latter soluble polymer.17
A
variety of conditions were probed to attach 4-carboxy-
benzaldehyde to the soluble polymer 7, and the best
results were obtained by using triethylamine as the base
and heating the reaction mixture in ethyl acetate to
90 ꢁC in a sealed tube (Scheme 2).18 Condensation of
pyrrole with excess of either benzaldehyde (9a), p-meth-
oxybenzaldehyde (9b), or 2-naphthylaldehyde (9c) with
BF3ÆEt2O in CH2Cl2 (similar to reported procedures
for normal porphyrin synthesis in solution)19 and subse-
quent oxidation with p-chloranil led to the formation of
the corresponding soluble polymer bound porphyrins
10a–c. Since the polymer is soluble in chloroform, the
Limitations in the use of solid polymers in synthetic
chemistry are pronounced by the difficulty in using
NMR to characterize intermediates, and the heteroge-
neous nature of the chemistry that could result in low
yields. However, soluble polymers can be used as an
alternate matrix for organic synthesis. These polymers
are non-cross-linked long chains, and exhibit both solu-
ble and insoluble characteristics depending on the sol-
vent used in the reaction.15 Synthetic approaches that
utilize soluble polymers couple the advantages of homo-
CHO
O
O
Cl
HO2C
CHO
Et3N / EtOAc
reflux, 2 h, 85%
2
1
CHO
H
N
(excess)
1.
,
O
NH
N
N
propionic Acid,
reflux, 4 h
O
HN
2. CH2Cl2, DDQ,
reflux, 2 h
tetraphenyl
porphyrin
in solution
3
+
=
solid polymer
NH
N
1. wash resin with CH2Cl2
HO2C
N
HN
2. NaOH, THF, reflux,
12 h, 6% (4 steps)
4
Scheme 1. Synthesis of mono-substituted porphyrins on insoluble polystyrene/divinyl benzene cross-linked polymer.

Q. Yang et al. / Tetrahedron Letters 46 (2005) 6737–6740
CHO
6739
n
m
HO2C
AIBN
+
PhH, reflux
Et3N / EtOAc
sealed tube (90 ºC)
7
5
6
Cl
Cl
O
9a R = Ph
9b R = p-OMePh
9c R = 2-Naphthyl
O
1. pyrrole / RCHO
BF3 Et2O, RT, 1 h
.
CHO
8
2. CH2Cl2, p-chloranil
R
RT, 2 h
O
NH
N
1. wash with MeOH
tetraphenyl
porphyrin
in solution
R
O
+
N
HN
2. NaOH, THF,
reflux, 12 h
10a-c
R
R
11a R = Ph 30% overall yield
NH
N
11b R = p-OMePh 16% overall yield
HO2C
R
11c R = 2-Naphthyl 15% overall yield
N
HN
=
soluble polymer
R
Scheme 2. Synthesis of mono-substituted porphyrins on soluble polystyrene polymer.
synthesis could be followed easily by 1H NMR. Figure 1
illustrates the H NMR of 10a. The peak broadening is
as a result of the size of the soluble polymer, however,
the porphyrin signals are clearly visible amongst the
polymeric resonances.
graphy step. The yields were calculated based on the
amount of bound aldehyde 8 used in the reaction. The
loading of the aryl aldehyde in 8 was calculated from
NMR integrations of the latter moiety versus the poly-
mer backbone signals. The mono-substituted porphyrin
acids were purified by silica column chromatography,
eluted with 3% methanol in CH2Cl2. Non-aromatic
aldehydes such as i-butyl aldehyde, propanal, and acet-
aldehyde did not yield any product, presumably due to
the polymerization of these reagents under the reaction
conditions.
1
The product in each case was isolated by basic hydroly-
sis of the ester functionality (2 N NaOH) to yield the
porphyrin acids 11a–c in yields comparable to solution
phase synthesis. However, in comparison to non-poly-
mer-supported solution phase synthesis, the purity of
the crude product is substantially improved, and each
product was easily purified by a simple silica chromato-
In conclusion, synthesis of porphyrins on polymeric
backbone can be used as a strategy to selectively
synthesize mono-substituted porphyrins without the
troublesome contamination from multiply-substituted
products.
polymer signals
Acknowledgment
Generous support was provided by the NSF-CAREER
(CHE-0094131). We are grateful to Professor Greg
Baker (MSU) for the use of his GPC.
porphyrin NH
bound porphyrin
signals
References and notes
1. Ogoshi, H.;Mizutani, T. Acc. Chem. Res. 1998, 31, 81–89.
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3
2. Huang, X.;Fujioka, N.;Pescitelli, G.;Koehn, F. E.;
Figure 1. 1H NMR of 10a. The polymer signals are due to the aliphatic
backbone and the aromatic side chains. The porphyrin signals can be
clearly seen, although they are broadened due to the large molecular
size of the soluble polymer.
Williamson, R. T.;Nakanishi, K.;Berova, N.
J. Am.
Chem. Soc. 2002, 124, 10320–10335.
3. Huang, X. F.;Nakanishi, K.;Berova, N. Chirality 2000,
12, 237–255.

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Q. Yang et al. / Tetrahedron Letters 46 (2005) 6737–6740
4. Huang, X.;Borhan, B.;Rickman, B. H.;Nakanishi, K.;
methanol was added. The precipitate was filtered and
redissolved with acetyl acetate. This cycle was repeated
until all the 4-carboxybenzaldehyde was removed. Mono-
substituted porphyrin 11a: to a mixture of the soluble
Berova, N. Chem. Eur. J. 2000, 6, 216–224.
5. Kurtan, T.;Nesnas, N.;Li, Y. Q.;Huang, X. F.;
Nakanishi, K.;Berova, N. J. Am. Chem. Soc. 2001, 123,
5962–5973.
polymer-supported aldehyde
8 (1 g, 0.27 mmol) and
6. Proni, G.;Pescitelli, G.;Huang, X. F.;Quraishi, N. Q.;
Nakanishi, K.;Berova, N. Chem. Commun. 2002, 1590–
1591.
7. Huang, X. F.;Rickman, B. H.;Borhan, B.;Berova, N.;
Nakanishi, K. J. Am. Chem. Soc. 1998, 120, 6185–6186.
8. The Porphyrins: Structure andSynthesis ;Dolphin, D., Ed.;
Academic Press: New York, 1979;Vols. 1–2.
9. Porphyrins andMetalloporphyrins ;Smith, K. M., Ed.;
Elsevier Scientific: New York, 1975.
10. Lavallee, D. K. The Chemistry andBiochemistry of
N-Substituted Porphyrins;VCH: New York, 1987.
11. Synthesis andOrganic Chemistry ;Kadish, K. M., Smith,
K. M., Guilard, R., Eds.;Academic Press: San Diego, CA,
2000;Vol. 1.
benzaldehyde (1.58 g, 15 mmol) in freshly distilled CH2Cl2
(30 mL) was added pyrrole (1.32 g, 20 mmol). Nitrogen
gas was purged into the solution with vigorous stirring,
and after 15 min, catalytic amount of BF3ÆOEt2 (0.1 mL)
was added. After 10 min, the solution turned from
colorless to amber. The reaction flask was shielded from
light with aluminum foil, and the reaction was stirred at
room temperature for another 1 h. Excess amount of p-
chloranil (3 g) was added to the solution, and it was stirred
for additional 2 h to generate the polymer-supported
porphyrin. The solvent was then removed under reduced
pressure and the residue was precipitated in cold methanol
to aid in removing the tetraphenylporphyrin side product
(not bound to polymer).
12. Lindsey, J. S. In The Porphyrin Handbook;Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.;Academic Press: San
Diego, CA, 2000, pp 45–118.
13. Leznoff, C. C.;Svirskaya, P. I. Angew. Chem., Int. Ed.
Engl. 1978, 17, 947.
14. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149–2154.
15. Wentworth, P.;Janda, K. D. Chem. Commun. 1999, 1917–
1924.
16. Chen, S. Q.;Janda, K. D. J. Am. Chem. Soc. 1997, 119,
11355.
To the solution of polymer-supported porphyrin in THF
(10 mL) was added 2 N NaOH aqueous solution (5 mL),
and the solution was refluxed overnight. After it was
cooled to room temperature, the pH of the mixture was
adjusted to 4 with 6 N HCl solution. The THF was
removed under reduced pressure, and the aqueous layer
was extracted with MeOH–CH2Cl2 (1:100, 3 · 20 mL)
until all the purple color was removed from the aqueous
layer. The organic layers were combined and the solvent
was evaporated. The residue was dissolved in CH2Cl2
(5 mL) and precipitated in cold methanol–THF (10:1).
This cycle was repeated three times. The solvent of the
combined organics was removed under reduced pressure,
and the residue was purified by column chromatography
(3% MeOH in CH2Cl2) to afford 53 mg (30%) of the pure
porphyrin acid 2 as a purple solid.
17. Yin, M.;Baker, G. L. Macromolecules 1999, 32, 7711–
7718.
18. Soluble polymer-supported aldehyde 8: soluble polymer
NCPS (2 g, 0.58 mmol), 4-carboxybenzaldehyde (0.9 g,
6 mmol) and Et3N (1 mL) were added to EtOAc (20 mL).
The reaction mixture was refluxed for 3 days. The reaction
was then cooled down and the solvent was rotovaped. The
oil like residue became a white powder as soon as cold
19. Lindsey, J. S.;Schreiman, I. C.;Hsu, H. C.;Kearney,
P. C.;Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827–836.