Facile meso functionalization of porphyrins by nucleophilic substitution with organolithium reagents

Article abstract of DOI:10.1002/(SICI)1521-3773(19980504)37:8<1107::AID-ANIE1107>3.0.CO;2-Z

The ruffle of the porphyrin increases with the number of meso substituents. (Octaethylporphyrin)nickel(II) undergoes nucleophilic substitution reactions upon treatment with alkylating reagents such as butyllithium, hydrolysis with water, and oxidation wit

Full text of DOI:10.1002/(SICI)1521-3773(19980504)37:8<1107::AID-ANIE1107>3.0.CO;2-Z

COMMUNICATIONS
[14] Although a decrease in the concentration of amine additive was
observed, we have not quantified the extent of its conversion into a
silylamine.
[15] If this mechanism is operative, it would require that the product amine
be liberated from the silicon polymer by exchange with primary
amine.
quent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ) gave the meso-butylporphyrin 2a in quantitative
yield. The reaction sequence formally proceeds as shown in
Equation (a).
O
[M(oep)]L!iR[M(oepLiR)]H!2 [M(oepHR)]D!DQ[M(oepR)]
(a)
[16] Certain mechanistic similarities exist between this process and
H2
Â
asymmetric dihydroxylation of olefins: J. S. M. Wai, I. Marko, J. S.
Svendsen, M. G. Finn, E. N. Jacobsen, K. B. Sharpless, J. Am. Chem.
Soc. 1989, 111, 1123 ± 1125.
The reaction is easily extended to a variety of different alkyl
and aryl reagents, including those that allow further chemical
modifications and coupling reactions. For example, reaction
of 1a with 2-(1,3-dioxane-2-yl)ethyllithium gave 2e in 70%
yield. The reaction is not limited to alkyllithium reagents, but
can also be used for the convenient introduction of aryl
groups. Reaction of phenyllithium with 1a gave 2 f in 65%
yield. Again, aryl substituents could be introduced which will
allow further chemical transformations. Compound 2h, whose
4-bromophenyl group is useful for other organometallic
coupling reactions, could be prepared from 1a with p-
bromophenyllithium in 40% yield. Introduction of the 2,5-
dimethoxyphenyl group in 2i, which proceeded in 65% yield,
is an example of the synthesis of donor± acceptor systems (by
formation of the benzoquinone). The free base porphyrins
substituted in the 5-position are available by demetalation of
the nickel(ii) complexes. For example, treatment of 2a with
concentrated sulfuric acid gave 2b in 75% yield.
Next, we turned out attention to the reactivity of different
metals in the same porphyrin. Treatment of 1b with butyl-
lithium under standard conditions gave the respective free
base 2b in 40% yield, while 1c and 1d could be converted into
the monobutylmetalloporphyrins 2c and 2d in 75 and 40%
yield, respectively. Even more surprising was the result that
free base porphyrins such as 1e could be treated directly with
butyllithium to give 2b in 50% yield or with phenyllithium to
give 2g in 90% yield. Presumably, this reaction proceeds by
initial formation of a dilithioporphyrin [Li2(oep)] of the type
Facile meso Functionalization of Porphyrins by
Nucleophilic Substitution with Organolithium
Reagents**
Werner W. Kalisch and Mathias O. Senge*
Dedicated to Professor Emanuel Vogel
on the occasion of his 70th birthday
It is generally accepted that the meso positions of porphy-
rins are the most reactive both for electrophilic and nucleo-
philic substitutions.[1] While several examples have been
described for SE reactions on porphyrins[1, 2] only scattered
attempts have been made to use SN reactions for the
modification of porphyrins. Published examples of the latter
all utilized some form of activated porphyrin, for example p-
radical cations or dications,[3] high-valent metal derivatives,[4]
or activated porphyrins with electron-withdrawing substitu-
ents.[5] Some of these reactions are suitable only for the
preparation of 5,5'-disubstituted dihydroporphyrins (phlor-
ins).[4b, 6] At best two substituents could be introduced with
electrophilic or nucleophilic reagents, and the methods were
limited with regard to the starting porphyrin or the introduc-
tion of different substituents.[7] To date, no general method
exists for the direct meso substitution of unactivated porphy-
rins with alkyl or aryl residues or for the introduction of more
than two substituents.
During a systematic study on the use of organometallic
reagents for C C coupling reactions, we found that octa-
ethylporphyrin (H2(oep); oep ˆ dianion of octaethylporphyr-
in) undergoes facile substitution reactions with organolithium
reagents; this allows the synthesis of a variety of porphyrins
with alkyl or aryl substituents at the meso positions. Treat-
ment of [Ni(oep)] (1a) with butyllithium (3 ± 4 equiv) be-
tween 80 and 1008C in THF followed by hydrolysis of the
intermediate (a Meisenheimer-type complex) provided the
corresponding 5-butyl-15-hydroporphodimethene. Subse-
[*] Priv.-Doz. Dr. M. O. Senge, Dipl.-Chem. W. W. Kalisch
Institut für Organische Chemie (WE02)
Fachbereich Chemie der Freien Universität
Takustrasse 3, D-14195 Berlin (Germany)
Fax: (‡49)30-838-4248
E-mail: mosenge@chemie.fu-berlin.de.
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Se543/2-4 and Heisenberg-Scholarship /3-1) and the Fonds der
Chemischen Industrie.
Angew. Chem. Int. Ed. 1998, 37, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3708-1107 $ 17.50+.50/0
1107

COMMUNICATIONS
described by Arnold.[8] With the exception of the reaction of
free base porphyrins with phenyllithium, nickel complexes
gave higher yields and were used for most reactions.
The reaction is not limited to the introduction of one meso
substituent. With butyllithium as reagent, 2a (lmax (CH2Cl2) ˆ
410, 572 nm) could be converted into a dialkylated product,
which was present as a regioisomeric mixture (3a, 70%,
lmax ˆ 427, 595 nm; 3b, 15%, lmax ˆ 423, 595 nm). The re-
gioisomers could be separated by chromatography and again
be used for another substitution/oxidation cycle with butyl-
lithium to yield 5,10,15-tributylporphyrin (3c) quantitatively
Figure 1. Side view of the molecular structure of 3c in the crystal.
Hydrogen atoms have been omitted for clarity. Selected bond lengths [Š]:
Ni N21 1.882(3), Ni N22 1.873(3), Ni N23 1.883(3), Ni N24 1.880(3); the
average deviation of the 24 macrocycle atoms from their least-squares
plane is 0.45 Š; the average deviation of the meso-carbon atoms from the
N-N-N-N plane is 0.93 Š; individual displacements of meso-carbon atom-
s [Š]: C5 0.94, C10 1.04, C15 0.94, C20 0.80.
variety of novel nonplanar porphyrins with tailor-made
distortion modes. As examples of porphyrins with mixed
substitution patterns, 5a was prepared from 2a in 50% yield
and 5b from 3a in 50% yield with use of 2,5-dimethoxy-
phenyllithium.
While working with the more sterically encumbered
porphyrins 3a ± d, we obtained brown side products in high
yield when the reaction temperature was allowed to rise
(lmax ˆ 441, 613 nm). A further reaction sequence starting
with butyllithium resulted in the conversion of 3c into 3d
(50%, lmax ˆ 459, 634 nm); porphyrin 4 was formed as a side
product (40%, lmax ˆ 451, 551 nm).
above
808C. These products were identified as 5,15-
Highly substituted porphyrins such as 3a ± d are of principal
interest with regard to studies on the conformational flexi-
bility of porphyrins.[9] Sterically encumbered dodecaalkylpor-
phyrins such as 3d cannot be obtained by conventional
porphyrin syntheses (acid-catalyzed condensation of pyrroles
and aldehydes followed by oxidation); instead, an unoxidiz-
able porphodimethene of unknown configuration is
formed.[9a] The structure of 3c, one of the highly substituted
alkylporphyrins we prepared, is shown in Figure 1.[10] The
macrocycle adopts a ruffled conformation, and the meso
positions are significantly displaced out of the plane (average
displacement of the meso-carbon atoms 0.93 Š). Despite the
presence of only three meso-butyl groups in 3c the confor-
mation is already more non-
dialkylporphodimethenes with syn-axial orientation of the
meso-alkyl substitutents. The molecular structure of the side
product 4 formed during the synthesis of 3d is shown in
Figure 2.[10, 11] These porphodimethenes could not be oxidized
to porphyrins with either DDQ or Br2. The exact structure of
the porphodimethene intermediates in our porphyrin syn-
thesis is still unknown. We assume that it might be different
planar than that in (pyri-
dine)[5,10,15,20-tetra(tert-
butyl)porphyrinato]zinc(ii)
(average displacement of the
meso-carbon atoms 0.9 Š),
the most nonplanar porphyr-
in with a ruffled conforma-
tion described so far.[9b]
Therefore, 3d will be even
more nonplanar. The syn-
thetic methodology present-
ed here should allow the
facile preparation of a wide
Figure 2. Side view of the molecular structure of 4 in the crystal. Only the
meso-hydrogen atoms are shown for clarity.
1108
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3708-1108 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 8

COMMUNICATIONS
10,20-H); d(3a) ˆ 0.60 (t, J ˆ 7.5 Hz, 6H, butyl-CH3), 0.77
(br s, 4H, butyl-CH2), 1.05 (m, 4H, butyl-CH2), 1.69, 1.75, 1.85
(each t, J ˆ 7.5 Hz, 24H, ethyl-CH3), 3.73 (br s, 16H, ethyl-
CH2), 4.27 (t, J ˆ 7.5 Hz, 4H, 5,10-CH2CH2CH2CH3), 9.05 (s,
2H, 15,20-H); d(3b) ˆ 0.53 (t, J ˆ 7.5 Hz, 6H, butyl-CH3),
0.85 (m, 6H, butyl-CH2), 0.93 (m, 4H, butyl-CH2), 1.65, 1.79
(each t, J ˆ 7.5 Hz, 24H, ethyl-CH3), 3.69 (br s, 16H, ethyl-
CH2), 4.29 (t, J ˆ 7.5 Hz, 4H, 10,20-CH2CH2CH2CH3), 9.05 (s,
2H, 10-20-H); d(3c) ˆ 0.58 (t, J ˆ 7.5 Hz, 6H, butyl-CH3),
0.65 (br s, 2H, butyl-CH2), 0.97 (br s, 4H, butyl-CH2), 1.04
(br s, 6H, butyl-CH2), 1.65, 1.75, 1.78, 1.79 (each t, J ˆ 7.5 Hz,
24H, ethyl-CH3), 3.44 ± 3.52 (m, 16H, ethyl-CH2), 4.03 ± 4.18
(m, 6H, CH2CH2CH2CH3), 8.77 (s, 1H, 20-H); d(3d) ˆ 0.59
(t, J ˆ 7.5 Hz, 12H, butyl-CH3), 0.73, 1.06 (each m, 6H,
CH2CH2CH2CH3), 1.74 (t, J ˆ 7.5 Hz, 24H, ethyl-CH3), 3.48,
3.58 (each br s, 16H, ethyl-CH2), 4.03 (m, 6H,
CH2CH2CH2CH3).
Received: October 27, 1997 [Z11087IE]
German version: Angew. Chem. 1998, 110, 1156 ± 1159
Keywords: alkylations ´ C ± C coupling ´ lithium
´ nucleophilic aromatic substitutions ´ porphy-
rinoids
Scheme 1. Synthesis of 8.
from the syn-axial structure of 4 and that the configuration of
the porphodimethene intermediates formed during the syn-
thesis of sterically encumbered porphyrins is of crucial
importance for the potential oxidation to the desired por-
phyrin.
[1] J.-H. Fuhrhop in The Porphyrins, Vol. I (Ed.: D. Dolphin), Academic
Press, New York, 1978, pp. 131 ± 159.
[2] a) R. Grigg, A. Sweeney, A. W. Johnson, J. Chem. Soc. Chem.
Commun. 1970, 1237 ± 1238; b) G. L. Closs, L. E. Closs, J. Am. Chem.
Soc. 1963, 85, 818 ± 819.
[3] K. M. Smith, G. H. Barnett, B. Evans, Z. Martynenko, J. Am. Chem.
Soc. 1979, 101, 5953 ± 5961, and references therein.
[4] a) J.-i. Setsune, T. Yazawa, H. Ogoshi, Z.-i. Yoshida, J. Chem. Soc.
Perkin Trans. 1 1980, 1641 ± 1645; b) H. Segawa, R. Azumi, T.
Shimidzu, J. Am. Chem. Soc. 1992, 114, 7564 ± 7565.
To study the reaction in more detail we utilized tetra-meso-
alkylporphyrins such as 6 as starting materials (Scheme 1).
Krattinger and Callot[6] showed that tetraphenylporphyrin
reacts with butyllithium under formation of a phlorin and
chlorin. Treatment of 6 with butyllithium at 1008C followed
by addition of water gave 7 in 90% yield (lmax ˆ 432, 525 nm).
Owing to the dialkylated meso position the porphodimethene
7 cannot be converted into a porphyrin. Nevertheless, treat-
ment of 7 with DDQ gave 8 in 80% yield (lmax ˆ 434, 541 nm);
here a meso- and an ipso-carbon atom were oxidized, leading
to a novel porphodimethene with an exocyclic double bond.
We are currently expanding the scope of this reaction towards
the synthesis of asymmetric porphyrins with mixed substitu-
ent types and towards biomimetic systems, and are studying
the reaction mechanism in more detail.
[5] L. C. Gong, D. Dolphin, Can. J. Chem. 1985, 63, 406 ± 411; X. Jiang,
D. J. Nurco, K. M. Smith, Chem. Commun. 1996, 1759 ± 1760.
[6] B. Krattinger, H. J. Callot, Chem. Commun. 1996, 1341 ± 1342;
Tetrahedron Lett. 1996, 37, 7699 ± 7702.
[7] a) J. W. Buchler, L. W. Puppe, Liebigs Ann. Chem. 1970, 740, 142 ±
163; b) A. Botulinski, J. W. Buchler, K.-L. Lay, H. Stoppa, ibid. 1984,
1259 ± 1269; c) A. Botulinski, J. W. Buchler, N. E. Abbes, W. R.
Scheidt, ibid. 1987, 305 ± 309; d) P. N. Dwyer, L. Puppe, J. W. Buchler,
W. R. Scheidt, Inorg. Chem. 1975, 14, 1782 ± 1785.
[8] J. Arnold, J. Chem. Soc. Chem. Commun. 1990, 976 ± 978.
[9] a) C. J. Medforth, M. O. Senge, K. M. Smith, L. D. Sparks, J. A.
Shelnutt, J. Am. Chem. Soc. 1992, 114, 9859 ± 9869; b) M. O. Senge, T.
Ema, K. M. Smith, J. Chem. Soc. Chem. Commun. 1995, 733 ± 734.
[10] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-100789. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[11] The formation of different configuration isomers for 5,5',15,15'-
substituted decaalkylporphyrins has been described by Buchler in
his elegant studies on the reductive alkylation of [Zn(oep)].[7] Crystal
structures of his stable porphodimethenes showed the same syn-axial
orientation of the meso-alkyl groups as described here for 4. See
ref. [7b ± d] and references therein.
Experimental Section
[Ni(oep)] (1a) (100 mg, 0.17 mmol) was dissolved in dried THF (60 mL)
and cooled to 708C. Within 10 min butyllithium (0.6 mmol, 0.3 mL of a
2m solution in cyclohexane) was added dropwise. The cold bath was
removed, and water (1 mL) in THF (5 mL) was added dropwise. The
reaction mixture was stirred for 10 min, DDQ (10 mL of a 0.06m solution in
dichloromethane) added, and the mixture stirred for another 20 min.
Finally, the reaction mixture was filtered through neutral alumina
(Brockmann grade I) and subjected to column chromatography on neutral
alumina (grade III) with hexane/CH2Cl2 (4/1) as eluant. Preparation of
higher alkylated porphyrins 3a ± d required lower temperatures ( 80 to
1008C) and less solvent.
UV/Vis and 1H NMR data for 2a and 3a ± d: UV/Vis (CH2Cl2): lmax(2a)
(lge) ˆ 410 nm (5.23), 535 (4.02), 572 (4.10); lmax(3a) (lge) ˆ 427 nm (5.19),
555 (4.09), 595 (3.99); lmax(3b) (lge) ˆ 423 nm (5.20), 552 (4.00), 595 (3.82);
lmax(3c) (lge) ˆ 441 nm (5.08), 570 (3.91), 613 sh (3.20); lmax(3d) (lge) ˆ
459 nm (4.93), 5.91 (3.92), 634 (3.56). 1H NMR (500 MHz, CDCl3): d(2a) ˆ
0.51 (t, J ˆ 7.5 Hz, 3H, butyl-CH3), 0.85 (m, 4H, butyl-CH2), 1.68, 1.74, 1.75,
1.85 (each t, J ˆ 7.5 Hz, 24H, ethyl-CH3), 3.79 (brs, 16H, ethyl-CH2), 4.42
(t, J ˆ 7.5 Hz, 2H, 5-CH2CH2CH2CH3), 9.32 (s, 1H, 15-H), 9.33 (s, 2H,
Angew. Chem. Int. Ed. 1998, 37, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3708-1109 $ 17.50+.50/0
1109