Hangman salophens

Article abstract of DOI:10.1021/ja042849b

We report here a modular approach for the construction of a new class of compounds, the Hangman salophens. In the Hangman motif, an acid-base functionality "hangs" over the face of a redox cofactor. In contrast to more synthetically intractable porphyrin-based Hangman systems, Hangman salophens permit the facile control of their proton and redox properties for the study of the proton-coupled electron transfer (PCET) activation of small molecules. By investigating the catalase-like disproportionation of H₂O₂, we show that the presence (1) of a strong proton-donating hanging group (i.e., carboxylic acid) and (2) of electron-donating groups on the redox-active salen imparts significant catalytic activity for the O-O bond activation of small molecule substrates. The contribution of the new ligand framework to furthering our understanding of how PCET can be implemented in the design of active/selective catalysts will be discussed. Copyright

Full text of DOI:10.1021/ja042849b

Published on Web 03/22/2005
Hangman Salophens
Shih-Yuan Liu and Daniel G. Nocera*
Department of Chemistry, 6-335, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge, Massachusetts 02139-4307
Received November 27, 2004; E-mail: nocera@mit.edu
Chart 1
The bond-making and bond-breaking catalysis of small-molecule
substrates in Nature are achieved by the coupled transport of both
protons and electrons.1-3 We have captured this proton-coupled
electron transfer (PCET) catalysis by designing synthetic constructs
that precisely position an acid-base functionality over the face of
a redox cofactor (Chart 1). In the Hangman porphyrin xanthene
(HPX),4 the catalase and epoxidation activities of the protoporphyrin
IX class of proteins and enzymes are emulated by using the acid
functional group to unmask the reactive high-valent metal-oxo
species by shuttling protons to a peroxide bound to the redox active
metalloporphyrin.5,6 Despite these advances, the elucidation of
structure/reactivity relationships of PCET catalysis is difficult when
porphyrins are used as the basal redox cofactor. Significant
challenges are posed by the lengthy and tedious preparation of
porphyrin platforms and their intractability to modular modifica-
tions. To develop a more versatile framework for studying PCET
catalysis, we thought to replace the porphyrin with a salophen as
the metal-supporting ligand.7-9 We envisioned that the X groups
of new Hangman salophen xanthene (HSX) ligands (Chart 1) could
be utilized to easily tune the properties of the redox platform. In
this communication, we show that HSX-metal complexes can be
readily assembled in a modular fashion and that indeed HSX redox
cofactors with properly tuned electronic properties can exhibit
exceptional catalase-type reactivity.
Scheme 1
The synthesis of HSX-ligands, as outlined in Scheme 1 and
described in Supporting Information, was designed about the
strategic disconnects indicated in Chart 1. One of the challenges
of the synthetic plan is the selective functionalization of the
symmetric xanthene bridge starting from the commercially available
xanthene dibromide 1.10-12 Using a two-step procedure, we could
convert 1 to the asymmetric xanthene dihalide 2.13 Selective Suzuki
cross-coupling of the more reactive aryl iodide bond with 4-meth-
oxycarbonylphenylboronic acid incorporates the hanging carboxylic
acid precursor to furnish 3.14 Subsequent cross-coupling of the
remaining aryl bromide with o-phenylene diamine boronic acid ester
affords 4.15 Hydrolysis of the methyl ester followed by condensation
with the corresponding salicyl aldehyde and subsequent complex-
ation with manganese diacetate provide the desired Hangman
salophen manganese complexes in a modular fashion.
Table 1. Turnover Numbers for the Dismutation of H2O2
Catalyzed by Manganese Salophen Complexes
catalyst
O2 yield/TONa
Mn-HSX-tBu
4372
98
373
86
472
62
Mn-EHSX-tBu
Mn-EHSX-tBub
Mn-Saloph-tBu
Mn-Saloph-tBub
Mn(OAc)2‚2H2O
a After 1 h. b In presence of 1 equiv of benzoic acid.
With a versatile synthetic route to the HSX framework in hand,
we are ideally positioned to address whether PCET catalysis can
be tuned by (i) the acid functional group and (ii) a redox-modulating
X group. To probe these issues, we chose to investigate the PCET
activation of O-O bonds by studying the disproportionation of
H2O2, an important PCET process that is catalyzed by a variety of
enzymes.16 As Table 1 shows, very high turnover numbers (TON)
for dioxygen production can be achieved at Mn-HSX platforms.
The presence of a strong proton donor dramatically increases
catalase-type reactivity. Whereas TON as high as 4372 can be
achieved with Mn-HSX-tBu, a relatively low TON is observed
when the carboxylic acid functionality is replaced by an ester (Mn-
EHSX-tBu). Similarly, control experiments with the redox-only
manganese salophen complex (Mn-Saloph-tBu) as well as with a
simple manganese salt (Mn(OAc)2‚2H2O) show low activity for
disproportionation. The addition of an external H+ source enhances
TON of the parent salen complex as well as the Mn-EHSX-tBu
complex, but the activity remains far inferior to that of Mn-HSX-
tBu, which manages the proton by intramolecular transfer from the
hanging functional group. An energy-minimized calculation of the
hydroperoxide-bound Hangman salophen complex reveals that the
hanging group is positioned over the face of the macrocycle and is
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10.1021/ja042849b CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Figure 1. Effect of electronic tuning on catalase-type reactivity in HSX-
Mn complexes: Mn-HSX-OMe (red 0), Mn-HSX-tBu (blue O), Mn-
HSX-NO2 (b).
to the redox processes occurring at the salophen platform. We show
here for H2O2 dismutation that a strong proton-donating hanging
group, working in concert with an electron-rich redox platform, is
essential for the activation of the O-O bond by PCET. In this way,
the Hangman salophens significantly contribute to investigations
of PCET catalysis because their modular design allows for the two
crucial components of a PCET reactionsacid-base and redox
propertiessto be tuned with facility. Accordingly, Hangman
salophens uniquely enrich the scope of multielectron PCET
reactions associated with catalytic bond-making and bond-breaking
chemistry of small molecule substrates.
able to hydrogen bond to substrate (Table S1 and Figure S1,
Supporting Information).
The data listed in Table 1 are consistent with the proposed
mechanism for the catalase activity of chloroperoxidases.16 Scheme
2 adapts the mechanism for the Hangman architecture. Coordination
of H2O2 to the metal results in a putative metal-bound hydroper-
oxide, which is converted into a Compound I intermediate by
proton-assisted heterolytic O-O bond cleavage. Deprotonation of
H2O2 followed by its oxidation by the high-valent metal-oxo
furnishes O2 and the reduced catalyst. The enhancement in TON
for the Mn-HSX-tBu catalyst is consistent with the proton-assisted
heterolytic O-O bond cleavage and/or the base-assisted production
of O2, thus accounting for the proton dependence of the PCET
catalysis.
Acknowledgment. We thank J. Bachmann for performing DFT
calculations and J. Y. Yang for fruitful discussions. This work was
supported by funding from the National Institutes of Health GM
47274.
We next explored whether the PCET catalysis of Scheme 2 is
affected by the electronic perturbation of the redox site. This issue
has not been probed for porphyrin-based Hangman platforms owing
to the difficulty associated with modifying the macrocycle.
Conversely, aromatic ring substituents on salen platforms are known
to influence the electronic properties of the metal and in turn dictate
the outcome of catalysis.17 Indeed, the electronic spectra of a series
of substituted HSX-manganese complexes reveal a strong sub-
stituent effect. The absorption spectra of the Mn-HSX complexes
(Figure S2) are distinguished by a low energy band in the visible
absorption spectrum similar to that observed for N,N′-di(3-tert-butyl-
5-methylsalicylidene) cyclohexanediamine manganese(III) chloride
in CH2Cl2.18 The band exhibits a significant red-shift along the series
Supporting Information Available: Synthesis, characterization,
and DFT calculations of Hangman salophens. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Chang, C. J.; Chang, M. C. Y.; Damrauer, N. H.; Nocera, D. G. Biophys.
Biochim. Acta 2004, 1655, 13-28.
(2) Stubbe, J.; Nocera, D. G.; Yee, C. S.; Chang, M. C. Y. Chem. ReV. 2003,
103, 2167-2202.
(3) Cukier, R. I.; Nocera, D. G. Annu. ReV. Phys. Chem. 1998, 49, 337-369.
(4) Yeh, C.-Y.; Chang, C. J.; Nocera, D. G. J. Am. Chem. Soc. 2001, 123,
1513-1514.
(5) Chng, L. L.; Chang, C. J.; Nocera, D. G. Org. Lett. 2003, 5, 2421-2424.
(6) Chang, C. J.; Chng, L. L.; Nocera, D. G. J. Am. Chem. Soc. 2003, 125,
1866-1876.
(7) Dalton, C. T.; Ryan, K. M.; Wall, V. M.; Bousquet, C.; Gilheany, D. G.
Top. Catal. 1998, 5, 75-91.
(8) Yamada, S. Coord. Chem. ReV. 1999, 190-192, 537-555.
(9) Katsuki, T. Synlett 2003, 281-297.
(10) Novick, J. S.; Ballester, P.; Ebmeyer, F.; Rebek, J., Jr. J. Am. Chem. Soc.
1990, 112, 8902-8906.
(11) Chang, C. J.; Deng, Y.; Heyduk, A. F.; Chang, C.-K.; Nocera, D. G. Inorg.
Chem. 2000, 39, 959-966.
(12) Hagadorn, J. R. Chem. Commun. 2001, 2144-2145.
(13) Chang, C. J.; Yeh, C.-Y.; Nocera, D. G. J. Org. Chem. 2002, 67, 1403-
1406.
X ) NO2 (λmax) 460 nm) < tBu (λmax) 490 nm) < OMe (λmax
)
511 nm). This trend parallels the increasing electron donation of
the X group and therefore is consistent with a salophen ligand-to-
metal charge transfer parentage for the absorption band. Strikingly,
these differently substituted HSX-manganese complexes display
dramatic reactivity differences in H2O2 dismutation. As illustrated
by the reaction profile of Figure 1, electron-donating substituents
significantly enhance catalyst performance. Mn-HSX-OMe (TON
) 4580) catalyzes the complete conversion of H2O2 in ∼20 min,
whereas a catalyst bearing a less donating substituent (X ) tBu)
converts 64% of substrate in the same time (TON ) 3060). On the
other hand, little to no reactivity is observed for Mn-HSX-NO2
(TON ) 81, 2% conversion). The presence of an electron-donating
group on the salophen of HSX platform19 appears to stabilize the
high-valent manganese-oxo intermediate against decomposition and/
or facilitates the heterolytic cleavage of the O-O bond.
(14) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59,
6095-6097.
(15) Deng, Y.; Chang, C. K.; Nocera, D. G. Angew. Chem., Int. Ed. 2000, 39,
1066-1068.
(16) Nicholls, P.; Fita, I.; Loewen, P. C. AdV. Inorg. Chem. 2001, 51, 51-
106.
(17) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Gu¨ler, M. L.; Ishida, T.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948-954.
(18) Feth, M. P.; Bolm, C.; Hildebrand, J. P.; Ko¨hler, M.; Beckmann, O.; Bauer,
M.; Ramamonjisoa, R.; Bertagnolli, H. Chem.-Eur. J. 2003, 9, 1348-
1359.
(19) Control experiments without a proton donor on a Hangman salophen
possessing electron-donating groups (Mn-EHSX-OMe) also show little
activity.
In conclusion, we have synthesized Hangman salophens as a new
ligand scaffold for PCET catalysis. The Hangman salophens are
distinguished from typical salophen constructs by the presence of
an intramolecular proton-transfer network, which is able to couple
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