Facile peripheral modification of N-confused porphyrin

Article abstract of DOI:10.1021/jo052188g

An improved methodology for the N-alkylation of the porphyrin isomer N-confused porphyrin is presented. The combination of polar solvent conditions and the use of the base Cs₂CO₃ affords externally modified products in high yield wit

Full text of DOI:10.1021/jo052188g

Facile Peripheral Modification of N-Confused
Porphyrin
Wenchao Qu, Tang Ding, Anil Cetin, John D. Harvey,
Michael J. Taschner,* and Christopher J. Ziegler*
Department of Chemistry, Knight Chemical Laboratory,
The UniVersity of Akron, Akron, Ohio 44325-3601
mjt1@uakron.edu; ziegler@uakron.edu
FIGURE 1. Structures of normal 5,10,15,20-tetraphenylporphyrin
(TPP), the internal tautomer of NCTPP free base (1i), and the external
tautomer of NCTPP free base (1e).
ReceiVed October 20, 2005
We have lately presented work on the synthesis, photophysics,
and metalation of the porphyrin isomer N-confused porphyrin
(NCP) (Figure 1).6 This macrocycle exhibits chemistry that is
significantly different from its normal porphyrin parent. One
notable characteristic of this species is that the nitrogen atom
at the periphery of the ring presents a tempting target for
functionalization. The modification of this position has been
examined, most simply with methyl iodide, resulting in an
external N-methylated NCP.7 Since then, there has been
additional work on the modification of metalated NCPs,8 but
the functionalization of free base NCPs remains largely unex-
plored.9 Recently, Chmielewski reported the alkylation of NCP
with a dibenzyl bromide,9b thus opening up the possibility of
using NCPs in larger covalent assemblies. We have been
working along similar lines trying to functionalize the external
nitrogen with various electrophiles.
An improved methodology for the N-alkylation of the
porphyrin isomer N-confused porphyrin is presented. The
combination of polar solvent conditions and the use of the
base Cs2CO3 affords externally modified products in high
yield without separation difficulties and without the use of
large excesses of alkylating reagent. The further transforma-
tion and metalation of these products provides opportunities
for the construction of metalloenzyme model complexes,
peptide adducts, and chromophore assemblies.
In this paper, we present an investigation into the function-
alization of the external nitrogen of free base NCP using various
alkylating agents. Under the optimized conditions, high yields
(6) (a) Furuta, H.; Asano, T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116,
767-768. (b) Chmielewski, P. J.; Latos-Graz˘yn´ski, L.; Rachlewicz, K.;
Glowiak, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 779-781. (c) Geier,
G. R., III; Haynes, D. M.; Lindsey, J. S. Org. Lett. 1999, 1, 1455-1458.
(d) Geier, G. R., III; Ciringh, Y.; Li, F.; Haynes, D. M.; Lindsey, J. S. Org.
Lett. 2000, 2, 1745-1748. (e) Srinivasan, A.; Furuta, H. Acc. Chem. Res.
2005, 38, 10-20. (f) Shaw, J. L.; Garrison, S. A.; Aleman, E. A.; Ziegler,
C. J.; Modarelli, D. A. J. Org. Chem. 2004, 69, 7423-7427 (g) Harvey, J.
D.; Ziegler, C. J.; Telser, J.; Ozarowski, A.; Krzystek, J. Inorg. Chem. 2005,
44, 4451-4453. (h) Harvey, J. D.; Ziegler, C. J. Chem. Commun. 2004,
1666-1667. (i) Harvey, J. D.; Ziegler, C. J. Chem. Commun. 2003, 2890-
2891. (j) Harvey, J. D.; Ziegler, C. J. Chem. Commun. 2002, 1942-1943.
(k) Harvey, J. D.; Shaw, J. L.; Herrick, R. S. Ziegler, C. J. Chem. Commun.
2005, 4663-4665. (l) Belair, J. P.; Ziegler, C. S.; Rajesh C. S.; Modarelli,
D. A. J. Phys. Chem. A 2002, 106, 6445-6451.
In the model chemistry of the heme proteins, there has long
been a focus on the functionalization of the periphery of
synthetic porphyrins. The most classic of such modified rings
is the picket fence porphyrin, which possesses a quartet of
sterically bulky groups around the outside of the macrocycle.1
This steric bulk results in the reversible binding of dioxygen in
the iron adduct, and this observation has spurred the develop-
ment of the peripheral organic chemistry of porphine.2 For
example, the cytochrome c oxidase work of Karlin and
co-workers involves a tetraphenyl porphyrin modified with an
appended copper-binding ligand.3 However, efforts in this area
are compounded by the difficulties associated with generating
such free base porphyrins4 or the separations of mixtures of
asymmetric macrocycles.5
(7) Chmielewski, P. J.; Latos-Graz˘yn´ski, L. J. Chem. Soc., Perkin Trans.
2 1995, 503-509.
(8) (a) Chmielewski, P. J.; Latos-Graz˘yn´ski, L.; Glowiak, T. J. Am. Chem.
Soc. 1996, 118, 5690-5701. (b) Ishikawa, Y.; Yoshida, I.; Akaiwa, K.;
Koguchi, E.; Sasaki, T.; Furuta, H. Chem. Lett. 1997, 453-454. (c) Furuta,
H.; Ishizuka, T.; Osuka, A.; Ogawa, T. J. Am. Chem. Soc. 1999, 121, 2945-
2946. (d) Furuta, H.; Ishizuka, T.; Osuka, A.; Ogawa, T. J. Am. Chem.
Soc. 2000, 122, 5748-5757. (e) Schmidt, I.; Chmielewski, P. J. Tetrahedron
Lett. 2001, 42, 1151-1154. (f) Schmidt, I.; Chmielewski, P. J. Tetrahedron
Lett. 2001, 42, 6389-6392. (g) Schmidt, I.; Chmielewski, P. J.; Ciunik, Z.
J. Org. Chem. 2002, 67, 8917-8927. (h) Schmidt, I.; Chmielewski, P. J.
Chem. Commun. 2002, 92-93. (i) Xiao, Z.; Patrick, B. O.; Dolphin, D.
Chem. Commun. 2003, 1062-1063. (j) Hung, C.-H.; Wang, S.-L.; Ko, J.-
L.; Peng, C.-H.; Hu, C.-H.; Lee, M.-T. Org. Lett. 2004, 6, 1393-1396. (k)
Ogawa, T.; Ishizuka, T.; Osuka, A.; Furuta, H. Angew. Chem., Int. Ed. 2004,
43, 5077-5081. (l) Chmielewski, P. J. Angew. Chem., Int. Ed. 2004, 43,
5655-5658.
(1) Collman, J. P. Acc. Chem. Res. 1977, 10, 265-272.
(2) Momenteau, M., Reed, C. A. Chem. ReV. 1994, 94 (3), 659-698.
(3) (a) Fry, H. C.; Cohen, A. D.; Toscano, J. P.; Meyer, G. J.; Karlin, K.
D. J. Am. Chem. Soc. 2005, 127, 6225-6230. (b) Kim, E.; Kamaraj, K.;
Galliker, B.; Rubie, N. D.; Moe¨nne-Loccoz, P.; Kaderli, S.; Zuberbu¨hler,
A. D.; Karlin, K. D. Inorg. Chem. 2005, 44, 1238-1247. (c) Ghiladi, R.
A.; Huang, H.; Moe¨nne-Loccoz, P.; Stasser, J.; Blackburn, N. J.; Woods,
A. S.; Cotter, R. J.; Incarvito, C. D.; Rheingold, A. L.; Karlin, K. D. J.
Biol. Inorg. Chem. 2005, 10, 63-67. (d) Kim, E.; Chufan, E. E.; Kamaraj,
K.; Karlin, K. D. Chem. ReV. 2004, 104, 1077-1134.
(4) Loppnow, G. R.; Melamed, D.; Hamilton, A. D.; Spiro, T. J. Phys.
Chem. 1993, 97, 8957-8968.
(5) Chou, H.; Chen, C.-T.; Stork, K. F.; Bohn P. W.; Suslick, K. S. J.
Phys. Chem. 1994, 98, 383-385.
(9) (a) Xiao, Z.; Dolphin, D. Tetrahedron 2002, 58, 9111-9116. (b)
Chmielewski, P. J. Org. Lett. 2005, 7, 1789-1792.
10.1021/jo052188g CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/22/2005
J. Org. Chem. 2006, 71, 811-814
811

TABLE 1. N-Alkylations of Free Base NCTPP 1
SCHEME 1. Synthesis of Externally N-Alkylated NCTPPs
ratio of reactants
1:Cs2CO3:2a-e
reaction
time (h)
%
yield
entry
substratea
1
2
3
4
5
6
2a
2a
2a
2a
2b
2b
2c
2d
2d
2e
1:0:90
16
2
2
2
30
2
20
24
6
46
45
52
96
38
43
69
45
61
80
1:1.5:2.0
1:1.5:2.0
1:3.0:4.0
1:0:5.0
1:1.5:2.0
1:3.0:4.0
1:0:1160
1:3.0:4.0
1:3.0:4.0
7
8b
9
10
16
a In entries 1 and 5, reaction solvent was CHCl3 and no base was used
in the reaction; in entry 2, the solvent is DMF; in entries 3, 4, 6, 7, 9, and
10, solvent is THF/DMSO; in entries 1 and 4 the reaction was conducted
at the 0.7 mmol scale, whereas in the other reactions the scale was 0.1
mmol. b In entry 8, 5 mL of allylbromide was mixed with 0.05 mmol of
NCP and no extra solvent was involved.
Similar to other modified analogues,7,9 the aromaticity of 3a is
weaker than that of its parent 1, since the aromatic region moves
back to 7-8.2 ppm from 7-9 ppm, and the internal CH and
NH upshift significantly from -5.0 and -2.42 ppm to 1.66 and
4.16 ppm, respectively (Figure 2). The product was of high
purity and formed crystals suitable for X-ray diffraction analysis
(vide infra).
Similarly, when a large excess of methyl-4-(bromomethyl)-
benzoate 2b or allylbromide 2d was reacted with 1, the
corresponding N-alkylated products were also obtained in 38%
and 45% yields, respectively (Table 1, entry 5 and 8). However,
these conditions have drawbacks: First, a large excess of
alkylating reagent is required, and at times separation of the
excess reagent can be difficult or tedious. Also, the use of an
excess of alkylating reagent often affords additional decomposi-
tion products.
of adducts have been obtained. In addition, these new macro-
cycles can be metalated using our established metal carbonyl
methods.6g-k The resultant compounds can then be used to
covalently couple molecules to the periphery of NCP for the
generation of novel model complexes and light-harvesting
arrays.3,10
In an effort to synthesize an externally N-alkylated NCP with
the potential for further functionalization, ethyl bromoacetate
2a was chosen as the alkylating reagent. Following the protocol
for N-methylation of NCP,7 the reaction of free base N-confused
tetraphenylporphyrin (NCTPP) 1 with a large excess of 2a was
carried out in CHCl3 under refluxing conditions, resulting in a
yield of 46% of NCTPP-ethyl acetate 3a (Scheme 1). The
formation of 3a from 1 was clearly evident from the analysis
In previous work,8g,9 bases such as Na2CO3, K2CO3 or
t-BuOK were used to promote the N-alkylation of NCP or its
metal complexes. This results in the need for a smaller excess
of alkylating reagent. For example, recently Chmielewski and
co-workers showed that only a 3-fold excess with 2 equiv of
base could afford a decent yield (55%) of a benzyl-alkylated
NCTTP product.9b While the above-described procedure has
been successful with certain reactions, it was found that these
conditions were not universal for all alkylating reagents. For
1
of the H NMR spectrum of 3a (CDCl3): the triplet at 1.17
ppm, quartet at 4.04 ppm, and singlet at 4.43 ppm showed that
the electrophile had been attached to the 2-nitrogen position.
FIGURE 2. 1H NMR of 3a (300 MHz, CDCl3). Asterisk (/) marks solvent and solvent impurities.
812 J. Org. Chem., Vol. 71, No. 2, 2006

FIGURE 3. X-ray structures with 50% thermal ellipsoids for 3a (a) and Co-3a (b) Hydrogen atoms have been omitted for clarity in the cobalt
structure.
SCHEME 2. Hydrolysis of NCP Derivative 3aa
as the base because it exhibits increased solubility and basicity
relative to K2CO3. When 1 (0.1 mmol) was combined with 2
equiv of ethyl bromoacetate 2a in the presence of 1.5 equiv of
Cs2CO3 in DMF at 75-80 °C for 2 h, the reaction solution
afforded 45% of the expected product 3a (Table 1, entry 2). In
an effort to avoid the use of high-boiling DMF, THF was
examined as a possible solvent. In THF, the reaction is slow
and only affords a small amount of product. However, after
∼4% DMSO (v/v) was added to the THF solution, the reaction
was complete in 1 h and afforded 52% (Table 1, entry 3).
Moreover, increasing the ratio of Cs2CO3 to 3.0 equiv and ethyl
bromoacetate to 4.0 equiv greatly improved the reaction yield
of 3a to 96% (Table 1, entry 4).
a Reagents and conditions: (i) LiOH, THF/H2O, reflux; (ii) acidification.
example, 3 equiv of 2b were reacted with 1 in the presence of
1.5 equiv of K2CO3 as the base in toluene. However, after 18
h of refluxing, little product formation was detected. This led
us to investigate and optimize the conditions for the alkylation
of the external nitrogen of 1, such that a variety of alkylating
reagents could be appended onto the macrocyle. In addition,
we sought to carry out these reactions with the free base, such
that we could use the modified macrocyles in later metalation
chemistry.
Following this result, three additional reagents for N-
alkylation of 1 were examined. Promising results were quickly
obtained without further optimization (Table 1, entry 6, 7, 9)
and indicate that THF/DMSO conditions should be broadly
applicable to a variety of alkylating reagents. Entries 1-9 in
Table 1 all involve halides activated by adjacent functionality.
To test whether NCP would react with halides other than methyl
iodide or functionality-activated halides, we chose to examine
iodopropane. Entry 10 in the table shows the result with this
reagent; although the reaction takes more time than the others
in the table, the yield of product is exceptionally high for a
porphyrin functionalization reaction (80%). With the successful
generation of compound 3a, we can readily hydrolyze it for
further functionalization of the periphery of NCP (Scheme 2).
The ester can be cleaved by using LiOH as the base in THF/
H2O, and the acid produced via acidification with HCl.
Some insight into the optimal reaction conditions was gained
by considering the tautomerization of the macrocycle in its
alkylation chemistry. As observed by Furuta and later confirmed
in our laboratory, 1 exhibits two tautomers depending on the
polarity of the solvent (Figure 1, 1i and 1e).11,6l With regard to
the alkylation of the peripheral nitrogen, the enamine-type
tautomer (1e) in the polar solvent should be more reactive than
the imine-type tautomer (1i). As a result, we believe that
alkylations in a polar solvent, such as DMF, should favor the
more reactive form and possibly afford more product than those
carried out in nonpolar media. In addition, polar solvents will
solubilize basic salts better than solvents such as toluene, which
produces a biphasic reaction with K2CO3. We chose Cs2CO3
In addition, peripherally functionalized NCPs can be meta-
lated by using previously established techniques.6g-k The
reaction of compound 3a with Co2(CO)8 produces a cobalt NCP,
and recrystallization from pyridine affords X-ray quality crystals
of Co(NCTPP-AcOEt)py Co-3a. The crystal structure of 3a
prior to metalation (Figure 3a) shows the presence of two
protons in the center of the macrocycle, similar to the structure
of the exterior tautomer 1e.11 The structure of the metalation
product (Figure 3b) correlates with an oxidation state assignment
of Co(II) based on the interior protonation state of the free base,
the coordination number of the metal, and the axial ligand bond
(10) (a) Kim, D.; Osuka, A. Acc. Chem. Res. 2004, 37, 735-745. (b)
Balaban, T. S. Acc. Chem. Res. 2005, 38, 612-623.
(11) (a) Furuta, H.; Ishizuka, T.; Osuka, A.; Dejima, H.; Nakagawa, H.;
Ishikawa, Y. J. Am. Chem. Soc. 2001, 123, 6207-6208. (b) Ishizuka T,
Furuta H. J. Synth. Org. Chem. Jpn. 2005, 3, 211-221.
J. Org. Chem, Vol. 71, No. 2, 2006 813

length.6h The successful metalation of 3a bodes well for the
construction of NCP-based metalloporphyrin model complexes.
In conclusion, the method that can functionalize the NCP
through N-alkylation has been optimized. By choosing THF/
4% DMSO as solvent and Cs2CO3 as the base, a variety of
modified NCPs can be produced in high yield without using a
large excess of reagent or base. The resultant products can be
readily isolated via chromatographic methods and can be
subsequently used in further organic transformations or meta-
lation reactions. Currently, this method is being expanded for
further modification of NCP with amino acids, chromophores,
and metal binding ligands.
to reflux for 2 h. After the TLC was checked and no NCTPP
reactant was left, the reaction mixture was allowed to cool to room
temperature and the solid was filtered off. Following removal of
the solvent, the residue was purified by flash chromatography on
a neutral alumina gel column (activity III). Decomposition impuri-
ties and a small amount of unreacted NCTPP were eluted with
benzene/hexanes solvent (80:20 v/v), and product was eluted with
benzene/CH2Cl2 (95:5 v/v). After the TLC plate was checked, the
pure product fractions were collected and solvent was removed to
1
give 470 mg (96%) of the NCP-ethyl acetate (3a). H NMR (300
MHz, CDCl3): δ 7.98-7.95 (m, 2H), 7.92-7.87 (m, 3H), 7.84-
7.80 (m, 3H), 7.73 (d, J ) 4.6 Hz, 1H), 7.68 (bs, 2H), 7.62-7.57
(m, 10H), 7.46 (d, J ) 4.6 Hz, 1H), 7.41 (d, J ) 4.6 Hz, 1H), 7.38
(bs, 3H), 7.2 (b, 1H), 4.43 (s, 2H), 4.16 (b, 1H), 4.04 (q, J ) 7.1
Hz, 2H), 1.66 (s, 1H), 1.17 (t, J ) 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 167.7, 164.3, 163.7, 155.1, 154.2, 144.1, 143.7,
141.8, 141.7, 141.3, 140.3, 136.8, 136.2, 135.3, 135.0, 134.5, 133.7,
133.5, 133.4, 133.1, 132.3, 131.8, 131.3, 131.2, 130.8, 129.7, 129.4,
128.5, 128.1, 128.0, 127.5, 127.4, 127.0, 125.0, 116.0, 115.5, 106.0,
61.7, 51.1, 14.2. UV-vis(CH2Cl2): λmax (ꢀ) 361 (45375), 446
(128000), 661 (11375), 716 (15250). MS (ESI) calcd for C48H37N4O2
([M + H]+) 701.8, found 701.2. HRMS (ESI) calcd for C48H37N4O2
([M + H]+) 701.2916, found 701.2901.
Experimental Section
General Procedure for the Synthesis of N-Alkylated N-
Confused Porphyrin 3a-e. Procedure 1. In a flame-dried 50 mL
two-neck round-bottom flask under nitrogen was dissolved 430 mg
(0.7 mmol) of NCTPP (1) in 10 mL CHCl3, and 2 mL of
ethylbromoacetate was added to this solution, which was stirred
and refluxed for 16 h. The reaction mixture was cooled to room
temperature, and solvent was evaporated under vacuum. The residue
was purified by flash chromatography on a basic alumina column
(activity III). Starting from benzene and gradually increasing
polarity by changing the ratio of benzene/CH2Cl2 from 100/0 to
20/80, the elute was collected and checked by TLC (alumina plate).
Green colored product fractions were combined together, followed
by removal of solvent to afford 228 mg (46.5%) of the NCP-ethyl
acetate (3a). Crystals of NCP-ethyl acetate suitable for X-ray crystal
structure analysis were obtained from a slow diffusion of MeOH
into a CH2Cl2 solution.
Acknowledgment. We wish to acknowledge NSF grant
CHE-0116041 used to purchase a Bruker-Nonius diffractometer
and the Kresge Foundation and donors to the Kresge Challenge
Program at The University of Akron for funds used to purchase
the NMR instruments used in this work. We also thank Dr.
Venkat Dudipala for his help with NMR spectroscopy.
Supporting Information Available: Synthetic procedures and
characterization for compounds 3a-e and X-ray crystallographic
tables for compounds 3a and its cobalt complex (CIF format).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Procedure 2. In a flame-dried 50 mL two-neck round-bottom
flask under nitrogen was dissolved 430 mg (0.7 mmol) of NCTPP
(1) in 20 mL THF and 0.8 mL of DMSO mixture, and 684 mg
(2.1 mmol) of Cs2CO3 and 0.31 mL (2.8 mmol) of ethylbromo-
acetate were added. The reaction mixture was stirred and heated
JO052188G
814 J. Org. Chem., Vol. 71, No. 2, 2006