Demetalation of metal porphyrins via magnesium porphyrins by reaction with grignard reagents

Article abstract of DOI:10.1002/chem.201301146

Novel transformations of metal porphyrins, such as nickel, zinc, copper, and silver porphyrins, to magnesium porphyrins are described. The reactions were accomplished by using 4-methylphenylmagnesium bromide in toluene. The scope of the reactions was wide

Full text of DOI:10.1002/chem.201301146

COMMUNICATION
DOI: 10.1002/chem.201301146
Demetalation of Metal Porphyrins via Magnesium Porphyrins by Reaction
with Grignard Reagents
Kei Murakami,[a] Yutaro Yamamoto,[a] Hideki Yorimitsu,*[a, b] and Atsuhiro Osuka*[a]
Many naturally occurring porphyrins play pivotal roles in
biological processes such as oxygen transport, oxygen stor-
age, and photosynthesis. In attempts to artificially mimic
these biological processes, a wide variety of porphyrin deriv-
atives have been synthesized and studied.[1] Amongst meta-
lated porphyrins, nickel porphyrins are the most widely em-
ployed building blocks in the construction of porphyrin-
based architectures[1,2] as diamagnetic nickel porphyrins can
be readily characterized by NMR spectroscopy. Additional-
ly, nickel porphyrins are chemically robust towards numer-
ous harsh reaction conditions. However, photoexcited states
of nickel porphyrins decay to the ground state within a few
hundred picoseconds.[3] Therefore, artificial constructs that
incorporate nickel porphyrins are inconvenient for the study
of photophysical properties. Conventionally, denickelation
of the compound of interest is necessary before assessing its
photophysical properties. Denickelation often requires
Scheme 1. Comparison of reactions of nickel porphyrin with arylmetal
reagents.
strongly acidic conditions. Typically, concentrated H2SO4 in
trifluoroacetic acid is employed, which can often lead to un-
desired decomposition of substrates.[4] Much milder proto-
cols for achieving denickelation are highly sought after.
During our studies on the functionalization of nickel por-
phyrins,[2n–p,5] we have serendipitously discovered that nickel
porphyrins are smoothly converted to the corresponding
magnesium porphyrins[6,7] upon treatment with 4-methylphe-
nylmagnesium bromide (Scheme 1, bottom). An interesting
observation worth noting is that no reaction occurred when
phenylmagnesium bromide was employed (Scheme 1,
middle).[8] In contrast, meso-arylation proceeds with more
nucleophilic aryllithium reagents (Scheme 1, top).[2a,c,9] The
denickelation/magnesiation reaction was applicable to a
wide variety of nickel porphyrins and the resulting acid-sen-
sitive magnesium porphyrins were readily transformed to
the corresponding free-base porphyrins via hydrolysis upon
treatment with aqueous 1m HCl. Overall, nickel porphyrins
are efficiently converted to free-base porphyrins in a two-
step methodology.[10]
Treatment of {5,10,15,20-tetrakisACTHNUGTRNEUNG[3,5-di(tert-butylphenyl)]-
porphyrinato}nickel (1Ni) with 4-methylphenylmagnesium
bromide in toluene at 258C for 4 h provided the correspond-
ing magnesium porphyrin 1Mg in 96% yield (Table 1,
entry 1). Further purification by recrystallization from
CH2Cl2/methanol afforded 1Mg in 76% yield. Concurrently,
4,4’-dimethylbiphenyl was also isolated, which indicates that
the displaced NiII was reduced to Ni0 by the Grignard re-
agent.[11] Note that addition of one equivalent of PPh3 com-
pletely suppressed the reaction.
In an attempt to assess the scope of the magnesiation re-
action, reaction conditions were screened. The magnesiation
reaction also proceeded smoothly in THF, albeit in slightly
lower yield (Table 1, entry 2). Porphyrins 1Ni and 1Mg did
not survive the addition of the Grignard reagent in dioxane.
We assume the decomposition of 1Ni and 1Mg in dioxane
was facilitated by the formation of a highly nucleophilic di-
[a] Dr. K. Murakami, Y. Yamamoto, Prof. Dr. H. Yorimitsu,
Prof. Dr. A. Osuka
Department of Chemistry, Graduate School of Science
Kyoto University Kitashirakawa, Sakyo-ku
Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3970
E-mail: yori@kuchem.kyoto-u.ac.jp
osuka@kuchem.kyoto-u.ac.jp
AHCTUNGTREGaNNNU rylmagnesium species generated by the Schlenk equilibri-
um (entry 3). No magnesium porphyrin 1Mg was observed
in the reactions performed in either ether or dichlorome-
thane (entries 4 and 5).
[b] Prof. Dr. H. Yorimitsu
Interestingly, the reaction was specific to 4-methylphenyl-
magnesium bromide. Only trace amounts of 1Mg were ob-
tained in the reactions with 3- and 2-methylphenylmagnesi-
ACT-C (Japan) Science and Technology Agency (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301146.
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Table 1. Optimization of the denickelation/magnesiation reaction.
Table 2. Scope of the denickelation reactions.[a]
RMgX
Solvent
Recovery
Yield
of 1Ni[a] [%]
of 1Mg[a] [%]
1
2
3
4
5
6
7
8
4-MeC6H4MgBr
4-MeC6H4MgBr
4-MeC6H4MgBr
4-MeC6H4MgBr
4-MeC6H4MgBr
3-MeC6H4MgBr
2-MeC6H4MgBr
4-MeOC6H4MgBr
PhMgBr
toluene
THF
dioxane
Et2O
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
0
0
0
78
75
96 [76][b]
74
<16
0
0
4
83
76
trace
quant
quant
75
0
0
0
0
9
10
11
iPrMgBr
Me3SiCH2MgCl
91
[a] 1H NMR yield. [b] Isolated yield.
um bromide (entries 6 and 7). Furthermore, no conversion
was observed when 4-methoxyphenylmagnesium bromide or
unsubstituted phenylmagnesium bromide[12] was employed
(entries 8 and 9). Other alkylmagnesium reagents such as
iPrMgBr and Me3SiCH2MgCl also failed to displace the cen-
tral nickel atom (entries 10 and 11).
The central magnesium atom of magnesium porphyrins
tends to be, in general, very labile in the presence of acid.
Magnesium porphyrin 1Mg was therefore easily trans-
formed to the corresponding free-base porphyrin under
mildly acidic conditions. Treatment of crude 1Mg in di-
chloromethane with 1m HCl aq at 258C for 4 h afforded the
corresponding product 1FB in 91% yield over the two steps
from 1Ni [Eq. (1)]. The reaction does not experience ad-
verse effects due to scale-up, as 1 g of 1Ni can be smoothly
converted to 1FB in high yield.
[a] Ar=3,5-(tBu)2C6H3; [b] 10 mm, 808C, 5 h, then 3m HCl; [c] 12.5 mm;
[d] 10 mm, 808C, 13 h, without 1m HCl; [e] 5 mm, 808C, 12 h.
ill effect by the conditions reported here. 5,15-Diarylpor-
phyrins 2cNi and 2dNi were also smoothly converted to the
corresponding free-base porphyrins 2cFB and 2dFB in 86
and 51% yields, respectively. The scope of magnesiation
does not stop at meso-substituted porphyrins. b-Substituted
nickel porphyrin 2eNi was also efficiently transformed to
2eFB in 71% yield. Note that magnesium porphyrin 2eMg
was more unstable than other magnesium porphyrins pro-
duced and 2eFB was obtained upon workup without retreat-
ment by 1m HCl. The reaction of nickel porphyrin dimer
2 fNi afforded the denickelated porphyrin 2 fFB in 59%
yield. For the reactions of 2bNi, 2eNi, and 2 fNi, a higher
temperature, diluted conditions, and longer reaction times
were required for the removal of the central nickel.
Recently, we reported that direct arylation reactions of
nickel porphyrins 2aNi provide b,b’-diarylporphyrins 3Ni.
Such arylation reactions are not applicable to zinc or free-
base porphyrins.[5a–c] The denickelation reaction of b,b’-di-
phenylated and b,b’-dinaphthylated porphyrins (3aNi, 3bNi,
and 3cNi) resulted in yields comparable to conventional
acid-induced denickelations (Table 3). The b,b’-dipyrenylat-
ed nickel porphyrin 3dNi was efficiently converted to 3dFB
by our two-step methodology in 55% yield, while only 10%
The denickelation reaction was applied to a wide variety
of nickel porphyrins (Table 2). The reaction of (5,10,15-tri-
ACHTUNGTRENNUNGarylporphyrinato)nickel 2aNi afforded 2aFB in 57% yield.
Free-base porphyrin 2bFB was furnished in 72% yield,
which suggests that sufficiently protected alkyne moieties
are compatible under magnesiation conditions. It is worth
noting that 2bNi decomposed under conventional conditions
(conc. H2SO4/TFA),[4] but was readily denickelated without
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Chem. Eur. J. 2013, 19, 9123 – 9126

Demetalation of Metal Porphyrins
COMMUNICATION
Table 3. Denickelation of diarylated nickel porphyrins.
not reactive at ambient temperature, the inner metals were
exchanged to magnesium at an elevated temperature with
prolonged reaction times. Unfortunately, our two-step meth-
odology is not applicable to porphyrins complexed with
cobalt and palladium. In both these cases, no reaction was
observed.
We have proposed a reaction mechanism for denickela-
tion (Scheme 2).[16] The reaction is initiated by nucleophilic
attack of the arylmagnesium reagent on the central nickel
atom of porphyrin A giving rise to nickelate[17] porphyrin B.
The nickel–nitrogen bond is then cleaved to allow for the
formation of a new magnesium–nitrogen bond (B to C). The
Ar’
(3Ni to 3FB)
Yield [%]
4-MeC6H4MgBr Conc. H2SO4/TFA
3aNi to 3aFB
3bNi to 3bFB
79
55
90
54[a]
3cNi to 3cFB
3dNi to 3dFB
57
55
70[a]
10[a]
[a] Ref. [5c].
of 3dFB was obtained using the standard sulfuric acid/tri-
fluoroacetic acid combination. The poor yield in the latter
case results from the instability of 3dFB under acidic
conditions.
Our two-step methodology can also be applied to por-
phyrins complexed with other metals. Zinc, copper, and
silver porphyrins could also be converted to the correspond-
ing magnesium porphyrin (Table 4). Treatment of zinc por-
phyrin 1Zn with 4-methylphenylmagnesium bromide in tol-
uene at 258C for 3 h afforded 1Mg in 84% yield.[13,14] Al-
though copper and silver porphyrins[15] (1Cu and 1Ag) were
Scheme 2. Proposed mechanism.
inner complexed metal is then exchanged for magnesium
forming intermediate D. Intermediate D then reacts with a
further equivalent of the arylmagnesium reagent to form
nickelate complex E. Finally, the remaining nickel–nitrogen
bond is broken to provide magnesium porphyrin F and di-
Table 4. Transformation of metal porphyrin to magnesium porphyrin.
AHCTUNGTREGaNNUN rylnickel(II). Fast reductive elimination affords nickel(0)
and the accompanying biaryl compound. We assume the
magnesiation of zinc, copper, and silver porphyrins follow a
similar mechanistic pathway.
In summary, we have developed an efficient two-step
methodology for the transformation of nickel-based por-
phyrins to the corresponding free-base porphyrins. The first
step involves the conversion of the nickel-based porphyrin
to the magnesium porphyrin, facilitated by treatment with
4-methylphenylmagnesium bromide. The magnesium por-
phyrins are then smoothly converted to the corresponding
free-base porphyrins under mildly acidic conditions. The
two-step methodology is also applicable to porphyrins com-
plexed with metals such as zinc, copper, and silver. Al-
though acid-induced demetalation[4] has been used for vari-
ous porphyrins, the scope of this classical procedure is limit-
ed as acid sensitive molecules or functional groups cannot
Metal
Toluene [mL]
T [8C]
t [h]
Yield[a] [%]
1
2
3
4
5
6
7
ZnII
CuII
CuII
AgII
AgII
CoII
PdII
2
2
0.5
2
0.5
2
25
25
100
25
100
100
100
3
4
24
4
1
12
19
84[b]
0[b]
93
5[b]
69
ND[c]
ND[c]
2
[a] Isolated yield. [b] 1H NMR yield. [c] Not detected.
Chem. Eur. J. 2013, 19, 9123 – 9126
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9125

H. Yorimitsu, A. Osuka et al.
Yorimitsu, A. Osuka, Asian J. Org. Chem. 2013, 2, 356; o) J. Song,
N. Aratani, H. Shinokubo, A. Osuka, J. Am. Chem. Soc. 2010, 132,
16356; p) J. Song, N. Aratani, J. H. Heo, D. Kim, H. Shinokubo, A.
Osuka, J. Am. Chem. Soc. 2010, 132, 11868.
survive the harsh conditions. The methodology described
herein is a much milder method for converting metalated
porphyrins to free-base porphyrins.
[3] a) D. Kim, C. Kirmaier, D. Holten, Chem. Phys. 1983, 75, 305; b) J.
Rodriguez, C. Kirmaier, D. Holten, J. Am. Chem. Soc. 1989, 111,
6500.
[4] J. K. M. Sanders, N. Bampos, Z. Clyde-Watson, S. L. Darling, J. C.
Hawley, H.-J. Kim, C. C. Mak, S. J. Webb, The Porphyrin Handbook,
Vol. 6, (Eds : K. M. Kadish, K. M. Smith, R. Guilard), Academic
Press, San Diego, 2000, Chapter 15.
[5] a) Y. Kawamata, S. Tokuji, H. Yorimitsu, A. Osuka, Angew. Chem.
2011, 123, 9029; Angew. Chem. Int. Ed. 2011, 50, 8867; b) S. Tokuji,
H. Awane, H. Yorimitsu, A. Osuka, Chem. Eur. J. 2013, 19, 64; c) Y.
Yamamoto, S. Tokuji, T. Tanaka, H. Yorimitsu, A. Osuka, Asian J.
Org. Chem. 2013, 2, 320; d) S. Anabuki, S. Tokuji, N. Aratani, A.
Osuka, Org. Lett. 2012, 14, 2778; e) H. Hata, H. Shinokubo, A.
Osuka, J. Am. Chem. Soc. 2005, 127, 8264.
[6] Preparation of magnesium porphyrins: a) J. S. Lindsey, J. N. Wood-
ford, Inorg. Chem. 1995, 34, 1063 and references therein; b) D. K.
Dogutan, M. Ptaszek, J. S. Lindsey, J. Org. Chem. 2007, 72, 5008.
[7] Only one report of demetalation/magnesiation reactions was pub-
lished on iron porphyrins: C. E. Castro, D. Kishore, J. Organomet.
Chem. 1985, 287, c27.
Experimental Section
The transformation in equation 1 is representative. Nickel porphyrin 1Ni
(56 mg, 0.05 mmol) was placed in a 10 mL Schlenk flask. The flask was
filled with nitrogen. Toluene (2 mL) was added to the flask. To the tol-
uene solution, 4-methylphenylmagnesium bromide (0.5 mL, 0.5 mmol, 1m
THF solution) was then added. The mixture was stirred at 258C for 4 h.
The reaction was quenched with 1m HCl aq. (0.5 mL) (note that attempts
to directly demagnesiate the intermediary porphyrin by addition of a
large excess of HCl always resulted in partial demagnesiation—without
the first addition of HCl, workup was complicated) and extracted with di-
chloromethane (5 mL) three times. The combined organic layer was
washed with brine and then dried over Na2SO4. After evaporation, the
crude solids were dissolved in dichloromethane (5 mL). To the solution,
1m HCl aq. was added and the resulting mixture was vigorously stirred at
258C. The reaction was monitored by TLC to complete the reaction in
4 h. The organic layer was separated from the aqueous layer and neutral-
ized by sat. aq. NaHCO3. The organic solution was then evaporated and
purified by silica-gel column chromatography to provide 1FB in 91%
yield (48 mg, 0.046 mmol).
[8] Selected examples on the reaction of nickel porphyrins with
Grignard reagents without denickelation/magnesiation: a) K.
Dahms, M. O. Senge, M. B. Bakar, Eur. J. Org. Chem. 2007, 3833;
b) K. Yoshida, S. Yamaguchi, A. Osuka, H. Shinokubo, Organome-
tallics 2010, 29, 3997; c) G. Li, A. Graham, W. Potter, Z. D. Gross-
man, A. Oseroff, T. J. Dougherty, R. K. Pandey, J. Org. Chem. 2001,
66, 1316.
Acknowledgements
[9] Selected very recent examples of synthesizing functionalized por-
phyrins with organolithium: a) M. O. Senge, C. Ryppa, M. Fazekas,
M. Zawadzka, K. Dahms, Chem. Eur. J. 2011, 17, 13562; b) M. O.
Senge, M. Fazekas, M. Pintea, M. Zawadzka, W. J. Blau, Eur. J. Org.
Chem. 2011, 5797; c) T. Takanami, S. Hayashi, K. Iso, J. Matsumoto,
F. Hino, Tetrahedron Lett. 2011, 52, 5345; d) S. A. Odom, S. Webster,
L. A. Padilha, D. Peceli, H. Hu, G. Nootz, S.-J. Chung, S. Ohira,
J. D. Matichak, O. V. Przhonska, A. D. Kachkovski, S. Barlow, J.-L.
Brꢁdas, H. L. Anderson, D. J. Hagan, E. W. V. Stryland, S. R.
Marder, J. Am. Chem. Soc. 2009, 131, 7510.
This work was supported by Grants-in-Aid from MEXT (nos. 22245006
(A), 20108006 “pi-Space”, 24685007, and 22406721 “Reaction Integra-
tion”). K.M. acknowledges JSPS Fellowships for Young Scientists. H.Y.
thanks the Kinki Invention Center for financial support.
Keywords: demetalation · Grignard reaction · magnesium ·
nickel · porphyrinoids
[10] Denickelation/lithiation of nickel porphyrins using large excess
amounts of lithium metal with ethylenediamine was reported: U.
Eisner, M. J. C. Harding, J. Chem. Soc. 1964, 4089.
[11] Fine particles of nickel metals were likely to be formed and were
easily separated by filtration through a pad of silica-gel.
[12] The reaction of 1Ni with phenylmagnesium bromide at 808C for 4 h
afforded 35% of 1Mg and no 1Ni was recovered.
[13] Senge reported that a demetalation reaction happened when zinc
porphyrin was treated with butyllithium: O. B. Locos, K. Dahms,
M. O. Senge, Tetrahedron Lett. 2009, 50, 2566.
[14] Zinc porphyrin 1Zn was much more reactive and less nucleophilic
phenylmagnesium bromide could be employed to afford 1Mg in
95% yield.
[15] Reductive demetalation of silver and copper porphyrins by NaBH4
has been reported, while examples were limited to octaethylpor-
phyrin and its derivatives: a) J. P. Collman, C. S. Bencosme, R. R.
Durand, Jr., R. P. Kreh, F. C. Anson, J. Am. Chem. Soc. 1983, 105,
2699; b) J. A. Cowan, J. K. M. Sanders, Tetrahedron Lett. 1986, 27,
1201.
[16] Single electron transfer from the Grignard reagent is also a possible
pathway as proposed in ref. [7].
[17] a) W. Kaschube, K. R. Pçrschke, K. Angermund, C. Krꢂger, G.
Wilke, Chem. Ber. 1988, 121, 1921; b) J. Terao, M. Tomita, S. P.
Singh, N. Kambe, Angew. Chem. 2010, 122, 148; Angew. Chem. Int.
Ed. 2010, 49, 144.
[1] a) Handbook of Porphyrin Science, Vols. 1–10 (Eds: K. M. Kadish,
K. M. Smith, R. Guilard), World Scientific Publishing, Singapore,
2010; b) Handbook of Porphyrin Science, Vols. 11–15 (Eds: K. M.
Kadish, K. M. Smith, R. Guilard), World Scientific Publishing, Sin-
gapore, 2011; c) Handbook of Porphyrin Science, Vols. 16–25 (Eds:
K. M. Kadish, K. M. Smith, R. Guilard), World Scientific Publishing,
Singapore, 2012; d) The Porphyrin Handbook, Vols. 1–10 (Eds:
K. M. Kadish, K. M. Smith, R. Guilard), Academic Press, San
Diego, 2000; e) Handbook of Porphyrin Science, Vols. 11–20 (Eds:
K. M. Kadish, K. M. Smith, R. Guilard), Academic Press, San
Diego, 2003; f) D. Dolphin, The Porphyrins, Vols. 1 and 2, Academic
Press, New York, 1979.
[2] a) M. O. Senge, Chem. Commun. 2011, 47, 1943; b) S. Horn, K.
Dahms, M. O. Senge, J. Porphyrins Phthalocyanines 2008, 12, 1053;
c) M. O. Senge, Acc. Chem. Res. 2005, 38, 733; d) H. Shinokubo, A.
Osuka, Chem. Commun. 2009, 1011; e) T. Ren, Chem. Rev. 2008,
108, 4185; f) B. M. J. M. Suijkerbuijk, R. J. M. Klein Gebbink,
Angew. Chem. 2008, 120, 7506; Angew. Chem. Int. Ed. 2008, 47,
7396; g) F. Atefi, D. P. Arnold, J. Porphyrins Phthalocyanines 2008,
12, 801; h) M. G. H. Vicente, K. M. Smith, J. Porphyrins Phthalocya-
nines 2004, 8, 26; i) W. M. Sharman, J. E. van Lier, J. Porphyrins
Phthalocyanines 2000, 4, 441; j) J. Setsune, J. Porphyrins Phthalocya-
nines 2004, 8, 93; k) S. Fox, R. W. Boyle, Tetrahedron 2006, 62,
10039; l) A. M. V. M. Pereira, S. Richeter, C. Jeandon, J.-P. Gissel-
brecht, J. Wytko, R. Ruppert, J. Porphyrins Phthalocyanines 2012,
16, 464; m) A. Satake, J. Synth. Org. Chem. Jpn. 2007, 65, 298; n) H.
Received: March 26, 2013
Published online: June 5, 2013
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