A mild, facile, one-pot synthesis of zinc azido porphyrins as substrates for use in click chemistry

Article abstract of DOI:10.1055/s-0033-1339694

The conversion of porphyrins bearing primary amines into zinc-protected azido porphyrins utilising a diazo-transfer reagent is reported. This method allows the mild, facile, and one-pot synthesis of zinc azido porphyrins bearing a range of meso functionalities, producing the required porphyrin in high yield. Reactivity of the azide functionality is demonstrated by subsequent model click reactions to produce triazole derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339694

1978▌
LETTER
lAetteMr ild, Facile, One-Pot Synthesis of Zinc Azido Porphyrins as Substrates for
Use in Click Chemistry
A Mild, Facile, One-Pot Synthesis of Zinc Azido Porphyrins
Francesca Bryden, Ross W. Boyle*
Department of Chemistry, The University of Hull, Cottingham Road, Hull, HU6 7RX, UK
Fax +44(1482)346511; E-mail: r.w.boyle@hull.ac.uk
Received: 30.05.2013; Accepted after revision: 25.06.2013
kyne moieties for use in the CuAAC reaction (see
Abstract: The conversion of porphyrins bearing primary amines
Dumoulin et al. for a comprehensive review of these
into zinc-protected azido porphyrins utilising a diazo-transfer re-
methods).9 Although a number of diverse procedures have
been exploited to date, in all cases the copper-catalyzed
agent is reported. This method allows the mild, facile, and one-pot
synthesis of zinc azido porphyrins bearing a range of meso function-
alities, producing the required porphyrin in high yield. Reactivity of nature of the CuAAC reaction necessitates inclusion of a
the azide functionality is demonstrated by subsequent model click
reactions to produce triazole derivatives.
porphyrin metallation step, in order to protect the central
cavity from copper insertion. While other metals can be
Key words: porphyrins, azides, zinc, click chemistry, diazotransfer
reagent
used, metallation with zinc is ubiquitous due to the ease of
both insertion and removal,9 while the d10 Zn2+ ion allows
the porphyrin to retain fluorescence and, via energy trans-
fer from the excited triplet state, singlet oxygen produc-
Since the introduction of the copper-catalyzed azide– tion.10 Conveniently, the diamagnetic nature of the zinc
alkyne cycloaddition (CuAAC) reaction as the definitive porphyrin complex also allows NMR analysis to be car-
example of a click reaction, the azide functional group has ried out.11
seen a meteoric rise in popularity.
Although synthesis of azide-functionalized porphyrins di-
rectly from azide-functionalised benzaldehydes12 is possi-
R1
Zn
R1
R1
Zn
R1
ble, a common method for introducing azide functional
groups into porphyrins is through conversion of a primary
amine into an azide, a reaction for which two methods are
reported in the literature.
R2
R1
N
N
N
N
N
N
N
N
N
N
R1
N3
N
R2
The most commonly utilized of these reactions is diazoti-
zation, utilising sodium nitrite in an acidic solvent to form
a diazonium salt intermediate, followed by immediate re-
action with sodium azide. While this method has been
shown to be rapid and effective, it requires harsh condi-
tions which are unsuitable for some functionalities, and
cooling to avoid degradation of the diazonium salt inter-
mediate.
Equation 1 Click reaction of an azido porphyrin
This is particularly true within the field of porphyrin
chemistry (Equation 1) which lends itself well to use of
the CuAAC reaction for a number of reasons; the insensi-
tivity to steric hindrance, mild reaction conditions, and
use of biphasic reaction mixtures for the CuAAC reaction
means that it is ideally suited to the conjugation of bulky
and lipophilic porphyrins with a range of substrates, in
particular biomolecules which may be highly water-solu-
ble and sensitive to harsh reaction conditions.1,2
An alternative to the diazotization method is the use of di-
azotransfer reagents such as azidotrimethylsilane.13 While
this is a less commonly utilised method, it allows for use
of milder reaction conditions, and a previously reported
example showed both similar yields and greater ease of
use.
However, when utilising either of these methods a sepa-
rate zinc-insertion step with additional purification is re-
quired after the formation of the azide, leading to
increased synthetic complexity and reduced yields.
Since publication of the first porphyrin click reaction in
2006,3 references have grown exponentially, with azide-
and alkyne-functionalized porphyrins being used to deco-
rate a range of structures, including nanoparticles,4 den-
drimers,5 polymers,6 solid silicon supports,7 and
fullerenes.8
The use of the diazo-transfer reagent imidazole-1-sulfo-
nyl azide hydrochloride has been previously demonstrat-
ed,14 utilising a copper-catalyzed conversion of a primary
amine into an azide on a range of aliphatic and aromatic
molecules. However, as this method was developed on
molecules insensitive to copper catalysts, it was inappro-
priate for use on porphyrin structures.
For this reason, numerous methods have been exploited in
order to functionalise porphyrins with both azide and al-
SYNLETT 21709013, 2415, 1978–1982
Advanced online publication: 14.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339694; Art ID: ST-2013-D0498-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Mild, Facile, One-Pot Synthesis of Zinc Azido Porphyrins
1979
Table 1 Synthesis of Zinc Azido Porphyrins from a Range of Amine-Functionalised Porphyrins19
R1
R1
O
S
NH+
–
N3
N
HSO4
N
N
N
N
NH
N
N
O
R1
R3
R1
R2
Zn
Zn(OAc)2, Et3N
HN
R1
R1
Entry
1
R1
R2
R3
Time (h)
17
Yield (%)a
94
N3
N3
NH2
NH2
Cl–
N+ Me
2
3
48
17
67
86
O
NH2
NH2
N3
N3
OMe
OMe
4
17
80
OEt
NH2
NH2
NH2
NH2
N3
N3
N3
N3
5
6
7
8
17
17
24
24
91
88
84
85
Cl
Br
I
9
17
48
92
87
NH2
N3
10
H2N
N3
11
12
13
3
3
92
98
86
N3
NH2
OEt
SO3
N3
NH2
Na+
–
NH2
N3
17
F
F
F
F
NH2
N3
F
14
17
88
a Isolated yields of pure products with compatible MS and 1H NMR spectral data.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1978–1982

1980
F. Bryden, R. W. Boyle
LETTER
R3
For this reason, we have developed a new method appro-
priate for use with porphyrin structures, utilising the imid-
azole-1-sulfonyl reactant (Table 1). Use of the hydrogen
sulfate salt of imidazole-1-sulfonyl azide allows for great-
er shock stability and storage than the HCl salt,15 and was
selected for this reason. While use of a copper catalyst is
problematic for porphyrins, use of alternative metal(II)
catalysts was also shown to be possible.14 An excess of a
zinc(II) catalyst therefore proved to be an effective way of
producing the desired zinc azido porphyrin in a one-pot
reaction.
N
N
N
N
R3
R3
R3
Zn
n = 0, 1
N3
R3
R3
While the use of methanol as a solvent for hydrophilic
porphyrins was found to be effective, a dichloromethane–
methanol solvent mixture was initially investigated for all
lipophilic porphyrins. In the case of porphyrins 7 and 8,
poor solubility in dichloromethane gave poorer yields and
longer reaction times, so a tetrahydrofuran–methanol sol-
vent system was used instead. A triethylamine base was
used for both lipophilic and hydrophilic porphyrins due to
ease of removal and miscibility with a wide range of sol-
vents.
N
N
Zn
n = 0, 1
N
N
N
N
N
R3
HCl in dioxane
The effectiveness of this new method was then demon-
strated on a range of porphyrin molecules (Table 1), in-
cluding both lipophilic and hydrophilic porphyrins
bearing a range of meso functionalities.16 The reaction
was shown to work well and under mild conditions on aryl
amines, and also on benzylic amines which cannot be con-
verted into azides through diazotization.
R3
N
HN
N
n = 0, 1
N
N
NH
N
Reaction times varied between different porphyrins, but in
the majority of cases reactions reached completion in 24
hours or less at ambient temperature and pressure. In only
two cases was it found necessary to employ longer reac-
tion times; for porphyrin 10 this was hypothesized to be as
a result of the increased steric hindrance. Porphyrin 2 also
required a longer reaction time, and gave only moderate
yields after 48 hours, which was attributed to the highly
electron-poor nature of the cationic porphyrin. In contrast,
both porphyrins 11 and 12 showed rapid reaction times
and excellent yields, due to the high reactivity of the ben-
zyl amine.
R3
Scheme 1 Model click reaction and zinc deprotection of five repre-
sentative porphyrins
Table 2 Model Click Reaction of Five Representative Porphyrins19
Entry
Starting porphyrin Click reaction Demetallation
yield (%)a
yield (%)a
15
16
17
18
19
3
4
96
93
87
86
70
76
93
81
76
86
Successful formation of the azides and their utility as in-
termediates in further functionalisation of five representa-
tive examples of the porphyrins was demonstrated by trial
click reactions using phenyl acetylene (Scheme 1).17 In all
cases, the click reaction was carried out successfully and
in good yield (Table 2) after microwave heating, with no
transmetallation from the copper catalyst observed.
8
11
14
a Isolated yields of pure products with compatible MS and 1H NMR
spectral data.
Removal of the zinc from the porphyrin cavity was then
demonstrated on all five model click compounds. In all
cases, the zinc was removed under mildly acidic condi-
tions at room temperature in five minutes18 and required
only an aqueous workup to purify.
tron-donating and electron-withdrawing groups. In most
cases, this reaction proceeded in excellent yields after stir-
ring under ambient conditions of temperature and pres-
sure, and straightforward workup procedure. Model click
reactions on five representative porphyrins, followed by
removal of the zinc metal from the porphyrin cavity
In conclusion, a facile, efficient, one-pot method to syn-
thesise a range of zinc-protected, azide-functionalised
porphyrins has been developed and tested on a range of li-
pophilic and hydrophilic porphyrins bearing both elec-
Synlett 2013, 24, 1978–1982
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Mild, Facile, One-Pot Synthesis of Zinc Azido Porphyrins
1981
(18) General Zinc-Removal Procedure for Porphyrins 15–19
In a typical experiment, to a solution the porphyrin (10.0 mg)
in CH2Cl2 (3 mL) was added HCl in dioxane (4 M, 0.5 mL)
and the mixture stirred at r.t. for 5 min. The mixture was
neutralised with sat. NaHCO3 solution, dried (MgSO4), and
the solvent removed under reduced pressure.
showed that the synthesized porphyrins successfully un-
dergo click reaction and facile demetallation.
Acknowledgment
Mass spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
(19) Spectroscopic Data
UV-Vis, HRMS, and 13C NMR data were obtained as
expected for all compounds.
Compound 1: 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, 2 H,
5-m-Ar), 7.77 (m, 9 H, 10,15,20-m,p-Ar), 8.22 (m, 8 H,
5,10,15,20-o-Ar), 8.87 (m, 8 H, β-H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Compound 2: 1H NMR (400 MHz, DMSO-d6): δ = 4.77 (s,
9 H, CH3), 8.27 (m, 4 H, 5-Ar), 9.09 (m, 14 H, 10,15,20-o-
Ar, β-H), 9.60 (m, 6 H, 10,15,20-m-Ar).
References and Notes
(1) Rostovtsev, V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(3) Devaraj, N. K.; Decreau, R. A.; Ebina, W.; Collman, J. P.;
Chidsey, C. E. D. J. Phys. Chem. B 2006, 110, 15955.
(4) Shetti, V. S.; Ravikanth, M. Eur. J. Org. Chem. 2010, 494.
(5) Zimmerman, S. C.; Elmer, S. L.; Man, S. Eur. J. Org. Chem.
2008, 3845.
(6) Chen, H.; Zeng, J.; Deng, F.; Luo, X.; Lei, Z.; Li, H.
J. Polym. Res. 2012, 19, 1.
(7) Palomaki, P. K. B.; Krawicz, A.; Dinolfo, P. H. Langmuir
2011, 27, 4613.
(8) Iehl, J.; Pereira de Freitas, R.; Delavaux-Nicot, B.;
Nierengarten, J.-F. Chem. Commun. 2008, 2450.
(9) Dumoulin, F.; Ahsen, V. J. Porphyrins Phthalocyanines
2011, 15, 481.
(10) Pavani, C.; Uchoa, A. F.; Oliveira, C. S.; Iamamoto, Y.;
Baptista, M. S. Photochem. Photobiol. Sci. 2009, 8, 233.
(11) Abraham, R. J.; Bedford, G. R.; Wright, B. Org. Magn. Res.
1982, 18, 45.
Compound 3: 1H NMR (400 MHz, CDCl3): δ = 4.11 (s, 9 H,
OCH3), 7.42 (m, 2 H, 5-m-Ar), 8.19 (m, 2 H, 5-o-Ar), 8.30
(m, 6 H, 10,15,20-m-Ar), 8.42 (m, 6 H, 10,15,20-o-Ar), 8.87
(m, 8 H, β-H).
Compound 4: 1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 9 H,
OCH3), 7.19 (m, 7 H, 10,15,20-p-Ar, 5-m-Ar), 7.55 (m, 3 H,
10,15,20-m-Ar), 7.66 (s, 3 H, 5-2-Ar), 7.80 (m, 3 H, 5-5-Ar),
8.88–9.03 (m, 8 H, β-H).
Compound 5: 1H NMR (400 MHz, CDCl3): δ = 1.61 (m, 9 H,
CH2CH3), 4.31 (m, 6 H, CH2CH3), 7.23 (m, 6 H, 10,15,20-
m-Ar), 7.35 (d, 2 H, J = 8.36 Hz, 5-m-Ar), 8.08 (m, 6 H,
10,15,20-o-Ar), 8.17 (d, 2 H, J = 8.36 Hz, 5-o-Ar), 8.89–8.98
(m, 8 H, β-H).
Compound 6: 1H NMR (400 MHz, CDCl3): δ = 7.44 (d, 2 H,
J = 8.36 Hz, 5-m-Ar), 7.75 (m, 6 H, 10,15,20-m-Ar), 8.14
(m, 6 H, 10,15,20-o-Ar),8.19 (d, 2 H, J = 8.16 Hz, 5-m-Ar),
8.96 (m, 8 H, β-H).
Compound 7: 1H NMR (400 MHz, CDCl3): δ = 7.41 (d, 2 H,
J = 7.96 Hz, 5-m-Ar), 7.94 (m, 6 H, 10,15,20-m-Ar), 8.08
(m, 6 H, 10,15,20-o-Ar), 8.18 (d, 2 H, J = 7.92 Hz, 5-o-Ar),
8.87 (m, 8 H, β-H).
(12) Rhee, J.-K.; Baksh, M.; Nycholat, C.; Paulson, J. C.;
Kitagishi, H.; Finn, M. G. Biomacromolecules 2012, 13,
2333.
(13) Shetti, V. S.; Ravikanth, M. Eur. J. Org. Chem. 2010, 494.
(14) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(15) Fischer, N.; Goddard-Borger, E. D.; Greiner, R.; Klapötke,
T. M.; Skelton, B. W.; Stierstorfer, J. J. Org. Chem. 2012,
77, 1760.
Compound 8: 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, 2 H,
J = 8.6 Hz, 5-m-Ar), 7.87 (m, 6 H, 10,15,20-m-Ar), 8.07 (m,
6 H, 10,15,20-o-Ar), 8.19 (d, 2 H, J = 8.36 Hz, 5-m-Ar), 8.84
(m, 8 H, β-H).
Compound 9: 1H NMR (400 MHz, CDCl3): δ = 7.23 (m, 1 H,
5-o-Ar), 7.52 (m, 1 H, 5-m-Ar), 7.75 (m, 10 H, 10,15,20-
m,p-Ar, 5-p-Ar), 7.96 (m, 1 H, 5-o-Ar), 8.21 (m, 6 H,
10,15,20-o-Ar), 8.87 (m, 8 H, β-H).
(16) General Synthesis of Porphyrins 1–14
In a typical experiment, zinc(II) acetate (50 mg) in MeOH
(2 mL) was added to a solution of the porphyrin (0.040
mmol) and Et3N (50 mg) dissolved in a suitable solvent
(CH2Cl2–THF for lipophilic porphyrins, MeOH for
hydrophilic porphyrins). Imidazole-1-sulfonyl azide
hydrogen sulfate (0.045 mmol) was added to the stirred
suspension, and the mixture stirred at r.t. until completion of
the reaction (TLC). The solvent was removed under reduced
pressure, and the product was purified by column
chromatography (normal-phase silica for lipophilic
porphyrins, reverse-phase silica for hydrophilic porphyrins).
(17) General Synthesis of Porphyrins 15–19
In a typical experiment, in a 10 mL microwave tube the
porphyrin (0.037 mmol) was dissolved in THF (7 mL) and
phenylacetylene (0.070 mmol) added. A solution of
copper(II) sulfate and sodium ascorbate (1 mg) in H2O
(1 mL) was added to the mixture and the mixture heated to
90 °C (MW) until complete consumption of the starting
material was observed on TLC. The solvent was removed
under reduced pressure, and the product purified by column
chromatography (normal phase).
Compound 10: 1H NMR (400 MHz, CDCl3): δ = 7.93 (m, 2
H, 5-4,5-Ar),7.75 (m, 10 H, 10,15,20-m,p-Ar, 5-3-Ar), 8.09
(m, 1 H, 5-o-Ar), 8.23 (m, 6 H, 10,15,20-o-Ar), 8.80–8.96
(m, 8 H, β-H).
Compound 11: 1H NMR (400 MHz, CDCl3): δ = 4.14 (s, 2
H, CH2),7.35 (d, 2 H, J = 7.76 Hz, 5-m-Ar) 7.74 (m, 9 H,
10,15,20-m,p-Ar), 8.15 (d, 2 H, J =7.72 Hz, 5-o-H), 8.23 (m,
6 H, 10,15,20-o-Ar), 8.85–8.98 (m, 8 H, β-H).
Compound 12: 1H NMR (400 MHz, CDCl3): δ = 1.61 (m, 9
H, CH2CH3), 4.31 (m, 6 H, CH2CH3),4.67 (s, 2 H, NH2), 7.25
(m, 6 H, 10,15,20-m-Ar), 7.65 (d, 2 H, J = 6.12 Hz, 5-m-Ar),
8.10 (m, 6 H, 10,15,20-o-Ar), 8.22 (d, 2 H, J = 6.32 Hz, 5-o-
Ar), 8.85–8.92 (m, 8 H, β-H).
Compound 13: 1H NMR (400 MHz, MeOH-d4): δ = 7.47 (d,
2 H, 5-m-Ar, J = 8.40 Hz), 8.26 (m, 18 H, 5-o-Ar, 10,15,20-
o,m-Ar), 8.85 (m, 8 H β-H).
Compound 14: 1H NMR (400 MHz, CDCl3): δ = 7.04 (d, 2
H, J = 8.36 Hz, 5-m-Ar), 8.09 (d, 2 H, J = 8.36 Hz, 5-m-Ar),
9.00 (m, 8 H, β-H).
Compound 15: 1H NMR (400 MHz, CDCl3): δ = 4.11 (s,
9 H, OCH3), 7.45 (m, 1 H, p-Ph), 7.55 (m, 2 H, m-Ph),
8.02 (m, 2 H, o-Ph), 8.20 (m, 2 H, 5-m-Ar), 8.32 (m, 6 H,
10,15,20-m-Ar), 8.43 (m, 8 H, 5,10,15,20-o-Ar), 8.52 (s, 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1978–1982

1982
F. Bryden, R. W. Boyle
LETTER
H, triazole), 8.86–8.93 (m, 8 H, β-H).
triazole H).
Compound 16: 1H NMR (400 MHz, CDCl3): δ = 3.96 (s, 9
H, OCH3), 7.31 (m, 3 H, 10,15,20-p-Ar), 7.43 (m, 1 H, p-
Ph), 7.52 (m, 2 H, m-Ph), 7.66 (m, 3 H, 10,15,20-m-Ar), 7.81
(m, 6 H, 10,15,20-o-Ar), 8.01 (m, 2 H, o-Ph), 8.18 (d, 2 H,
5-m-Ar, J = 8.6 Hz), 8.40 (d, 2 H, 5-o-Ar, J = 8.4 Hz), 8.49
(s, 1 H, triazole), 8.84–9.03 (m, 8 H, β-H).
Compound 18: 1H NMR (400 MHz, CDCl3): δ = 5.90 (s, 2
H, CH2), 7.35 (m, 1 H, p-Ph), 7.44 (m, 2 H, m-Ph), 7.63 (m,
2 H, o-Ph), 7.70 (m, 9 H, 10,15,20-m,p-Ar), 7.87 (d, 2 H, J =
7.76 Hz, 5-m-Ar), 8.03 (s, 1 H, triazole), 8.18 (m, 8 H,
5,10,15,20-o-Ar), 8.76–8.89 (m, 8 H, β-H).
Compound 19: 1H NMR (400 MHz, CDCl3): δ = 7.42 (m, 1
H, p-Ph), 7.55 (m, 2 H, m-Ph), 8.01 (m, 2 H, o-Ph), 8.18 (d,
2 H, J = 8.96 Hz, 5-m-Ar), 8.37 (d, 2 H, J = 8.98 Hz, 5-m-
Ar), 8.59 (s, 1 H, triazole H), 8.89–9.02 (m, 8 H, β-H).
Compound 17: 1H NMR (400 MHz, THF-d8): δ = 6.41 (m,
1 H, p-Ph), 6.53 (m, 2 H, m-Ph), 7.01 (m, 6 H, 10,15,20-m-
Ar), 7.13 (m, 2 H, o-Ph), 7.17 (m, 6 H, 10,15,20-o-Ar), 7.42
(m, 4 H, 5-o,m-Ar), 7.90–8.00 (m, 8 H, β-H), 8.16 (s, 1 H,
Synlett 2013, 24, 1978–1982
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.