Controlling both ground- and excited-state thermal barriers to Bergman cyclization with alkyne termini substitution

Article abstract of DOI:10.1021/ja045979t

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd⁰ catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c-e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a-d undergo zinc insertion upon treatment with Zn(OAc)₂·2H₂O in CHCl₃/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a-d) in 70-92% yields. Thermal Bergman cyclization of 1a-e and 2a-d was studied in chlorobenzene and ～35-fold 1,4-cyclohexadiene at 120-210 °C. Compounds 1b and 2b with R = H react at lower temperature (120 °C) and produce cyclized products 3b and 4b in higher yields (65-70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the -TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 °C in chlorobenzene/CHD for 24 h. Photolysis (at λ ≥ 395 nm) of 1b and 2b at 10 °C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 °C in the dark. Unlike thermolysis at 125 °C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c: 5%; 4c: 8% based on ¹H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 °C with λ ≥ 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation. Copyright

Full text of DOI:10.1021/ja045979t

Published on Web 12/17/2004
Controlling Both Ground- and Excited-State Thermal Barriers to Bergman
Cyclization with Alkyne Termini Substitution
Mahendra Nath, Maren Pink, and Jeffrey M. Zaleski*
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received July 6, 2004; E-mail: Zaleski@indiana.edu
Porphyrins are ubiquitous molecular constructs because of their
potential in biomedical applications such as photodynamic therapy1,2
and the ability to incorporate their electronic properties into optical
devices.3,4 In line with this trend, coupling reactive functionalities
into strong porphyrinic chromophores has potential for the develop-
ment of novel biomedical reagents that can be triggered optically
at long wavelengths, without the need for external chemical
cofactors.
Attempts to photochemically cyclize simple enediynes5-9 have
been restricted to UV excitation, partially because of the lack of a
suitable chromophore with extinction in the visible spectral region.
In addition, traditional acyclic enediynes are generally more difficult
to activate than their carbocyclic10 or metallocyclic10,11 counterparts,
exhibiting restrictively high activation barriers. This work focuses
Figure 1. X-ray structure of 1c and 4b (from photoreaction of 2b). Thermal
ellipsoids are illustrated at 50% probability.
on modulating thermal and photochemical activation barriers of
porphyrinic enediynes.
The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphe-
nylporphyrin with the corresponding organostannanes in the pres-
ence of Pd0 catalyst in THF at reflux temperature yields free base
2,3-dialkynylporphyrins 1a,c-e (Scheme 1).12-14 The subsequent
deprotection of trimethylsilyl group of 1a with TBAF in THF under
aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphe-
nylporphyrin 1b in 87% yield.13 Compounds 1a-d undergo zinc
insertion upon treatment with Zn(OAc)2‚2H2O in CHCl3/MeOH to
give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a-
d) in 70-92% yields (Scheme 1).
Table 1. Thermal Bergman Cycloaromatization of 1a-e and
2a-d
compounds
reaction conditions
1a or 2a (%)
3b or 4b (%)
1a: R ) TMS
1b: R ) H
1b: R ) H
1c: R ) Ph
1d: R ) Pr
1e: R ) iPr
2a: R ) TMS
2b: R ) H
2b: R ) H
2b: R ) H
2c: R ) Ph
2d: R ) Pr
C6H5Cl, CHD, 190 °C, 24 h
C6H6, iPrOH, 25 °C, 72 h
C6H5Cl, CHD, 120 °C, 8 h
C6H5Cl, CHD, 200 °C, 30 h
C6H5Cl, CHD, 160 °C, 24 h
C6H5Cl, CHD, 190 °C, 24 h
C6H5Cl, CHD, 190 °C, 24 h
C6H5Cl, CHD, 120 °C, 8 h
C6H6, iPrOH, 50 °C, 72 h
C6H6, iPrOH, 25 °C, 72 h
C6H5Cl, CHD, 210 °C, 30 h
C6H5Cl, CHD, 160 °C, 24 h
95
98
-
-
-
65
50
55
60
-
70
6
-
30
45
30
-
10
96
-
92
96
60
40
Scheme 1. Dialkynylporphyrinic Enediynes and Their Bergman
Cyclization Reactivities
a Recovered starting compounds 1a-e or 2a-d. b Isolated yields of
cyclized products 3b-e or 4b-d.
120-210 °C (Table 1). Compounds 1b and 2b react at lower
temperature (120 °C) and produce cyclized products 3b and 4b in
higher yields (65-70%) than their propyl, isopropyl, and phenyl
analogues, with R ) Ph being the most stable. Continuing in this
trend, the -TMS derivatives 1a and 2a exhibit no reactivity even
after heating at 190 °C in chlorobenzene/CHD for 24 h.
The conjugated porphyrin-enediyne framework is ideal for
determining whether electronic excitation of the chromophore is
capable of activating a relatively stable, acyclic enediyne unit.
Photolysis (at λ g 395 nm) of 1b and 2b at 10 °C leads to the
formation of isolable picenoporphyrin products in 15 and 35%
yields, respectively, in 72 h, whereas these compounds are stable
under identical conditions in the dark at 25 °C (Table 2).
The crystal structure of 1c (Figure 1) reveals a near-planar
porphyrin backbone with an alkyne termini distance (C24‚‚‚C24A)
of 3.658 Å. To assess the thermal reactivities of 1a-e and 2a-d,
thermal Bergman cyclization temperatures have been evaluated in
solid state by differential scanning calorimetry (DSC). Single
exotherms are observed for each compound over a wide range of
temperatures (1b: 160 °C; 1a: 388 °C), indicating a substantial
difference in the activation barriers to Bergman cyclization within
the series. For R ) H and R ) Ph, sharp exotherms are observed
∼100 °C apart (1c: 257 °C; 2b: 172 °C; 2c: 272 °C), revealing
a dependence of cyclization reactivity on the steric bulk of the
R-group. Thermal Bergman cyclization of 1a-e and 2a-d was
also studied in chlorobenzene and ∼35-fold 1,4-cyclohexadiene at
The crystal structure of photoproduct 4b (Figure 1) displays a
mixed ruffle/saddle distorted porphyrin fused to a planar piceno
unit.12-14 Remarkably, the formation of Bergman cyclized product
4b from acyclic enediyne 2b is not restricted to high-energy
photoexcitation. Rather, photolysis of 2b at 10 °C at longer
9
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10.1021/ja045979t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Photo-Bergman Cycloaromatization of 1 and 2a
) H,13 but the high temperature of the R ) Ph cyclization reaction12
suggests that it is not for R ) Ph. The pronounced dependence of
the reaction on R reveals that the barrier to the 1,4-diradical
compounds
reaction conditions
1bb or 2bb (%)
3bc or 4bc (%)
1b: R ) H
C6H6, iPrOH, 10 °C,
hν (λ g 395 nm), 72 h
C6H6, iPrOH, 10 °C,
hν (λ g 395 nm), 72 h
C6H6, iPrOH, 10 °C,
hν (λ g 515 nm), 72 h
C6H6, iPrOH, 10 °C,
hν (λ g 590 nm), 120 h
45
15
q
intermediate is smaller for R ) H than that for R ) Ph (∆HR)H
< ∆HR)Phq) and is therefore controlled at least in part by the steric
bulk of the R-group at the alkyne termini. This is supported by
computational studies that suggest a ∼15 kcal/mol difference in
∆Gq for such a substitution.16 Similarly, photoexcitation into the
Soret and Q-bands populates the 1ππ* manifold, ultimately leading
to formation of Bergman product in respectable yields for R ) H
(35% at 10 °C) and in trace amounts for R ) Ph at 125 °C, once
again reflecting differential activation barriers as a function of
R-group ([∆HR)Hq]* < [∆HR)Phq]*). In this case, cyclization can
occur along either the excited singlet or triplet surface via an excited
diradical species,8,17,18 the subsequent intermediates derived from
which remain unclear. It is important to highlight that [∆HR)Hq]*
2b: R ) H
2b: R ) H
2b: R ) H
35
65
85
35
15
6
a Photo-Bergman cyclization of 1a,c-e, 2a,c,d (entries 1, 4-7, 11, and
12 in Table 1) was attempted in benzene/iPrOH at 10 °C with λ g 395 nm
light for 72 h, but starting material was recovered quantitatively. b Recovered
starting material. c Isolated yields of cyclized product.
wavelengths (λ g 515 or 590 nm) in benzene/iPrOH (4:1, 72 h)
produces 4b in 15 and 6% isolated yields, respectively. Photolyses
of 1a,c-e and 2a,c,d were also performed under the same reaction
conditions, but in all cases, starting material was recovered in
quantitative yield.
To probe whether the activation barriers to Bergman cyclization
in the excited state follow the same trend as those in the ground
state, photolyses of 1c and 2c were performed at elevated
temperature (125 °C). Unlike thermolysis at 125 °C, which did not
yield Bergman cyclized product for R ) Ph, photolysis generates
q
< ∆HR)H and [∆HR)Phq]* < ∆HR)Phq, which reveals that in
addition to having the same energetic relationships in the ground
and excited states, the thermal barriers in the excited states are lower
than those in the ground states overall. Finally, conjugation of the
enediyne unit into the porphyrin electronic transitions leads to
sufficient distortion to not only generate photoproduct with λ g
395 nm (Soret) excitation, but with longer wavelength, Q-band
excitation (λ g 515, 590 nm) as well. This suggests that it may be
possible to extend photoelectronic activation of enediynes well out
into the visible spectral region, enhancing the potential for such
frameworks as photodynamic therapy agents in hypoxic environ-
ments.
1
small amounts of picenoporphyrin (3c: 5%; 4c: 8% based on H
NMR) as well as a mixture of reduced porphyrin products that were
not separable. While some photoproduct was formed at elevated
temperature, compounds 1c and 2c with R ) Ph are still consider-
ably more stable than 1b and 2b with R ) H, which leads to
photoproduct in up to 35% yield at 10 °C. Thus, trends in the
barriers to the Bergman cyclization step in the excited state have
similar relationships to those in the ground state (from DSC and
product isolation) as a function of the R-group.
Acknowledgment. The support of the National Institutes of
Health (R01 GM62541-01) is gratefully acknowledged.
Supporting Information Available: Experimental details and
characterization data for 1c-e, 2a-d, 3b-d, and 4b-d as well as
X-ray crystallographic data for 1c and 4b (PDF, CIF, plain text). This
material is available free of charge via the Internet at http://pubs.acs.org.
The picture that emerges from this work is shown in Scheme 2.
Scheme 2. Reaction Profile for Ground- and Excited-State
Bergman Cyclization of 1b-c and 2b-c
References
(1) See, for example: (a) Detty, M. R.; Gibson, S. L.; Wagner, S. J. J. Med.
Chem. 2004, 47, 3897. (b) Macdonald, I. J.; Dougherty, T. J. J. Porphyrins
Phthalocyanines 2001, 5, 105.
(2) Bonnett, R. Chem. Soc. ReV. 1995, 19.
(3) Holten, D.; Bocian, D. F.; Lindsey, J. S. Acc. Chem. Res. 2002, 35, 57.
(4) Drain, C. M.; Hupp, J. T.; Suslick, K. S.; Wasielewski, M. R.; Chen, X.
J. Porphyrins Phthalocyanines 2002, 6, 243.
(5) Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil,
T. L. J. Am. Chem. Soc. 1996, 118, 3291.
(6) Kaneko, T.; Takahashi, M.; Hirama, M. Angew. Chem., Int. Ed. 1999,
38, 1267.
(7) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35,
8089.
(8) Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
(9) Purohit, A.; Wyatt, J.; Hynd, G.; Wright, J.; El-Shafey, A.; Swamy, N.;
Ray, R.; Jones, G. B. Tetrahedron Lett. 2001, 42, 8579.
(10) Rawat, D. S.; Zaleski, J. M. Synlett 2004, 393.
(11) Basak, A.; Mandal, S.; Bag, S. S. Chem. ReV. 2003, 103, 4077.
(12) Aihara, H.; Jaquinod, L.; Nurco, D. J.; Smith, K. M. Angew. Chem., Int.
Ed. 2001, 40, 3439.
(13) Nath, M.; Huffman, J. C.; Zaleski, J. M. Chem. Commun. 2003, 858.
(14) Nath, M.; Huffman, J. C.; Zaleski, J. M. J. Am. Chem. Soc. 2003, 125,
11484.
(15) Cramer, C. J. J. Am. Chem. Soc. 1998, 120, 6261.
(16) Prall, M.; Wittkopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comput. Chem.
2001, 22, 1605.
(17) Clark, A. E.; Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001,
123, 2650.
Thermolysis along the ground-state potential surface leads to
generation of the typical 1,4-phenyl diradical intermediate presumed
to be singlet in origin.15 In the presence of H-donor, a subsequent
activated process leads to production of picenoporphyrin by radical
addition to the adjacent meso-phenyl rings and subsequent rearo-
matization by loss of H2.12-14 The latter step is rate limiting for R
(18) Clark, A. E.; Davidson, E. R. J. Am. Chem. Soc. 2001, 123, 10691.
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