Oxygen-Oxygen Bonds:
Catalytic Redox Pathways in Energy Storage
ARCHIVES
MAS
SINS
OF TECHNOLOGY
by
JUN 0 8 2009
Stephen D. Fried
LIBRARIES
Submitted to the Department of Chemistry
as a supplement to the requirements for the degree of
S.B. in Chemistry
at the
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
May 2009
© Stephen Fried. All rights reserved.
The author hereby grants to MIT permission to reproduce and disseminate paper
and electronic copies of this thesis document in whole or in part.
2_OC
Date:
Author:
7
phen D. Fried
Certified by
P
e ranie GNoera
essor Daniel 'GNo era
Date:
Date:
Accepted b y: -
Y: Professor Sylvia T. Ceyr
,
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E
Acknowledgment of the Author.
To my Teachers;
It has been less than four years since I have entered the field of chemistry,
and yet by now it already seems to me as though my choice of major at MIT was this
inevitable, obvious thing imbued into me as a sort of educational predestination.
And yet, the intellectual journey is anything but preordained; such illusions
underscore the fact that we students have an unfortunate - albeit seemingly
irrepressible - capacity to underestimate the influence that our teachers have on
our curiosities, dispositions, and sense of wonder toward Nature.
Having acknowledged this, I would like to thank my professors: those who
shaped my mind and challenged me to question. Some of these individuals do not
know the effect they have had on my scientific development, as many of them had
no direct role in shaping the research that I have accomplished as an undergraduate.
It is on their behalf, however, that I aspire to a career in academic science and
research, and can stand so steadfast by this conviction.
As a freshman, I declared my major in chemistry and tried my first go at
research through the UROP program in the laboratory of Professor Daniel Nocera. I
cannot express how few assets I could provide the laboratory at this incipient stage,
but was nonetheless drawn - somewhat blindly, I must admit - by my perception
that scientists must address the question of renewable energy generation. Professor
Nocera deserves only my deepest gratitude for inspiring me by example toward this
calling, and for allowing me the opportunity to engage in experimental chemical
-2-
research during my four years as an undergraduate student addressed toward this
modern-day challenge. Professor Nocera paired me initially with gradate student
Dr. Joel Rosenthal, who provided me with the research problem addressed in
Section II. It must be mentioned that much of the synthetic work had been
accomplished before my arrival, and the structures presented could not have come
into being without the extensive study conducted previously by Joel and
Christopher Chang.
I thank my family, who have supported my endeavors in these past four
years at MIT, and who have had to partially manage on my behalf the travails that
are attached to this journey. I may not become the original "doctor" that they had in
mind, but I hope that this "other" doctorate in my future may be pleasing in their
sight as well.
Finally, I reserve for last, my great acknowledgement of the mentorship and
guidance of my post-doc adviser of two years, Dr. Matthew Kanan. It would be quite
difficult to describe in words his indomitable patience and the tremendous impact
he has played in shaping my research career. He performed a large portion of the
organic synthesis and characterization detailed in Section III, and my own
contributions inevitably reflect his skills through his conferring them unto me. As of
this writing, we will both soon be continuing research in separate paths at Stanford
University, and I very much hope to continue obtaining invaluable advice and
inspiration from him as we remain in proximity in the coming years.
-3-
Table of Contents.
Acknowledgement of the Author...................................................................................2
I.
General Background: 0-0 Bonds, Energy, and Related Concepts.....................5
II.
H20 2 Dismutation by "Hangman"-Porphyrin Artificial Catalases....................15
2005 to 2006.
...................................... 15
1. Introduction .................................................
22
.........
2. R esu lts ..............................................................
....................................... 2 7
3. Discussion ....................................................
III.
Studies Toward an Organic 0-0 Bond Forming Catalyst via Bisindole...........31
Carboxylates
2006 to 2008.
..................................... 31
1. Introduction ..................................................
37
2. Monom er Results ......................................................
3. Bridged Bisindole Results...............................................
4. Target Catalytic Cycle......................................
.
........
53
....................................... 56
5. Discussion ....................................................
IV. Supplementary Information.................................................62
63
1. Synthesis of Hangman Catalysts (Section II) ....................................
66
2. Time Course Plots of Hangman Catalysts (Section II) ...........................
68
3. Characterization Data of Bisindoles (Section III) .................................
73
4. Synthesis of Bisindoles (Section III) ..........................................
82
5. NMR spectra of Bisindoles (Section III) .......................................
126
Th e Auth or....................................................................
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I. General Background.
The present understanding of energy - its many forms, and its governing role
in the time evolution of physical systems - underlies many of the most fundamental
and unifying principles furnished by scientific theories. We are now deeply aware
that energy is inherently quantized and is associated with stationarystates (from
quantum theory), that it is conserved (from the first law of thermodynamics), but
that its conversion is asymmetric and not invariant to time reversal (from the
second law of thermodynamics). The transaction of energy from one system to
another system; from one form to another form, is deeply embedded in our
interpretation of Nature, and refining what precisely energy is tells a large portion of
the story that is Science.
In contrast, energy technologies allow mankind to harvest (by converting the
form of) natural "banks" of energy - primarily the chemical bonding energy of
organic molecules in reduced states - in order to perform tasks to our liking: there
are many such tasks, but a significant portion of them involves the transformation
-5-
into electricity. It is certain that one of the most significant challenges facing
developed society in the 21st century will be devising how to derive energy in the
form of electricity in large quantities from sources other than fossil fuels. Because
fossil fuels have been used so monolithically, new methods of providing useful
energy without them have gone undeveloped until only the last few decades. A
large number of efforts in scientific research from a panoply of disciplines today are
motivated by this challenge.
There are many ways of addressing such a far-reaching problem, but one
attractive and thoughtful strategy to probe it is to consider by what means all the
chemical energy that has been harvested from fuels since the Industrial Revolution
was "made" in the first place. Essentially all terrestrialbanks of energy are derived
originally from solar radiation, and the development of the photosynthetic process
by cyanobacteria some 3.5 billion years ago,1 which (in general terms) couples light
energy to drive endothermic electron transfer reactions, is perhaps the most
significant development in geological history. However, how this solar energy is
actually used and stored in nature is intimately tied to the chemical bond between
two oxygen atoms.
The common theme that ties my research projects in the Nocera group in the
past four years is an interest in systems that transfer energy through the making
and breaking of oxygen-oxygen bonds. 0-0 bonds are some of the weakest
1 Blankensip, RE. Photosynth. Res., 1992, 33, 2, 91-111.
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covalent bonds in nature, with bond dissociation enthalpy (BDE) values near 33 kcal
mol-1 in H2 0 2 . By simple thermodynamic arguments, the formation of these bonds
from energy-rich O-H and C=O bonds is uphill, and the consumption of these bonds
in reactions that oxidize other reagents are exothermic, and if not carefully
controlled, explosive. Indeed Nature decided to employ the free energy liberated by
the reduction of molecular 02 to obtain the vast majority of energy available to
aerobic heterotrophic organisms via respiration. Presently, the highly active area of
fuel cell technology is tied intrinsically to a question that cells had to answer long
ago in evolutionary history: how does one maximize an output potential (i.e.,
minimize the overpotential) generated by the reduction of 02 with H2 as reductant? 2
Nature's own fuel cell, cytochrome c oxidase (CcO), evolved to drive the complete
reduction of 02 by an "H2 equivalent" in the form of NADH (the reduced form of
nicotinamide adenine dinucleotide), which is exothermic by 1.229 electron volts
(eV) per elementary charge transferred as shown on the left side of Scheme 1. An
incomplete reduction of 02 leads to the formation of hydrogen peroxide
2Winter,
M.; Brodd, RJ. Chem. Rev., 2004, 104, 4245-4270.
-7-
(H202),
although this transformation's change in free energy involves less than half of the
energy evolved by the complete reduction of 02 and the formation of water.3 Watersplitting and 02 reduction, which revolve around forming and cleaving 0-0 bonds,
is the foundation by which energy in biological systems is stored and released,
respectively. By improving the catalytic efficiency of these fundamental processes,
and by coupling their chemistry to the more robust energy reservoirs of sugars,
nature harnessed a means of cumulatively retaining solar radiation energy in
chemicals, and in so doing, engineered its own sustainable energy solution.
Potentially, a viable energy solution for humans could operate in a parallel logic;
with large-scale light harvesting (via photovoltaics), storage by water splitting (with
electrolyzers), and utilization by a so-called hydrogen economy. Hydrogen as a fuel
E
0=0
Fuel
+0.695 V
e
2H, +0,
HO- OH
Q,,
+1.229 V
s
+1.778 V
2e + 2H+
Work Heat
Electncry
SolarEnergy
9000 x
energy demand
2H2O
10' mol/yr
2 HO'H
Scale dictates the use of water
Scheme 1. Left: the reduction products of 02 - the energetic basis of a fuel cell. Right: a
paradigm of sustainable energy for society based on nature's (photo credit: M. Kanan).
substrate is a means to store energy for intermediate periods of time. It is an
electricity-equivalent that is stored without battery in conjunction with fuel cells,
3 Bard, AJ; Parsons, R; Jordan, J. StandardPotentialsin Aqueous Solution; Marcel
Dekker: New York, 1985.
-8-
and a substrate capable of sequestering carbon dioxide by the reverse Water-Gas
Shift reaction and the Fischer-Tropsch reaction. 4
The thermodynamic nature of a given 0-0 bond and a particular reduction
product (whether it be R-OH, H2 0, or M=O) is fixed, as in all chemical reactions, by
only the identities of reactants and products. The question of what course the
chemical reaction takes, through which intermediates, in which energy regimes, and
at what time scales, all describe the kinetics of the reaction, and 0-0 bond
formation and cleavage chemistry demands the use of a catalyst for its effective
execution, meaning that the mechanistic subtleties matter immensely. From an
energetics perspective, the amount of energy required in forming 0-0 bonds, and
the amount released upon their reduction, depends in large part on the
orchestration of the multi-electron processes that are tethered inherently to
charged intermediates, high in energy without the assistance of an appropriate
catalytic framework
In biological systems, energy-rich transformations (either storage or release)
are coupled to the reduction and oxidation (abbreviated as redox hereafter) of small
molecules, in nearly all cases enabled via coupling proton transfer to electron
(a) Schulz, H.Appl. Cat.A, 1999, 186, 1-2, 3-12. (b) Mahajan, D; Goland, AN. Cat.
Today, 2003, 84, 1-2, 71-81. (c) Schultz, K; Bogart, L; Besenbruch, G; Brown, L;
Buckingham, R; Campbell, M; Russ, B; Wong, B. "Hydrogen and Synthetic
Hydrocarbon Fuels-a Natural Strategy." Proc.Nat.Hydrogen Assoc. Meeting, 2006.
4
-9-
transfer (i.e., proton-coupled electron transfer, PCET).5 A consummate example is
the oxidation of water in Photosystem I1,6 where the energy barrier is surmounted
via photonic inputs that activate a series of intermediate states in the oxygenevolving complex (OEC). 7 PCET continues to emerge as a mechanistic theme in a
vast array of natural systems outside the photosynthetic context; such as
11
10
cytochrome c oxidase,8 copper-based oxidases, 9 hydrogenases, and nitrogenases.
In qualitative terms, the role that PCET plays can be described as preventing
the accumulation of net charge at any discrete spatial-temporal coordinate of the
reaction by triggering protonation in conjunction with reduction, and deprotonation with oxidation. A simple illustrative example from Meyer's work
12
concerns a redox couple between aqueous RuIV/I' complexes. Meyer reported that
at pH 7, the thermodynamic potential for oxidation of cis-[Ru'I(bpy)2(py)(H20)]
2
+
2
(bpy = 2,2'-bipyridine; py = pyridine) to cis-[Ru"'(bpy)2(py)(OH)] + is 0.66 V vs. NHE
s Chang, CJ; Chng, LL; Nocera, DG. J.Am. Chem. Soc., 2003, 125, 1866-76.
6 For further general reading on this highly developed subject: (a) Dismukes, GC.
Science, 2001, 292, 447-8. (b) Tommos, C; Babcock GT. Acc. Chem. Res., 1998, 31,
18-25. (c) Ruettinger, W; Yagi, M; Wolf, K; Bernasek S; Dismukes GC. ]. Am. Chem.
Soc., 2000, 122, 10353-10357.
7 A similarly voluminous work is available on the biological OEC and attempts at
molecular models thereof. See especially: (a) Barber, J; et al. Curr. Opin. Struct.Biol.,
2001, 14, 447. (b) Limburg, J; et al. Science, 1999, 283, 1524. (c) Renger, G.
Biochim. et Biophys. Acta., 2004, 1655, 195-204.
8 Gennis, RB. Proc.Natl. Acad. Sci U.S.A., 1998, 95, 12747-12749.
9 Solomon, EI; Chen, P; Metz, M; Lee, S-K; Palmer, AE. Angew. Chem. Int. Ed., 2001,
40, 4570-4590.
10 Thauer, RK; Klein, AR; Hartmann, GC. Chem. Rev., 1996, 96, 3031-3042.
11 (a) Burgess, BK; Lowe, DJ. Chem. Rev., 1996, 96, 2983-3011. (b) Rees, DC;
Howard, JB. Curr.Opin. Chem. Biol., 2000, 4, 559-566.
12 (a)Binstead, RA; McGuire, ME; Dovletoglu, A; Seok WK; Roeckler LE; Meyer TJ. ].
Am. Chem. Soc., 1992, 114, 173-186. (b) Trammell, SA; Wimbish, JC; Odobel, F;
Gallagher LA; Narula PM; Meyer TJ.]. Am. Chem. Soc., 1998, 120, 13248-49.
-10-
- note the change in oxidation state as well as the number of protons. However,
when the mechanism involved initial electron transfer (without alteration of the
molecule's atomic composition) to give cis-[Ru"'(bpy)2(py)(H20)] 3+,1.04 V is
required. Similarly, the thermodynamic potential for oxidation of cis[Ru"'I(bpy)2(py)(OH)] 2+to cis-[Ruwv(bpy)2(py)(0)] 2+is 0.74 V, but without proton
transfer, cis-[Rul'(bpy) 2(py) (OH)]
3+requires
>1.6 V.
When non-metal molecules undergo redox chemistry, these mechanisms are
critical because of the lack of latitude such systems have toward diverse oxidation
states. 13 Especially when the molecules in question are small, the challenge
becomes even greater because charged intermediates, possessing diminished
orbital bases to delocalize the charge, are even higher in energy yet. The question of
small molecule activation is for this reason, among others, one of the grand
challenges of catalytic chemistry.
Small molecule activation and redox catalysis interface one another in the
oxidation of water:
2H 20
= 02 + 4H+ + 4e
(1)
Catalysis for this seemingly simple reaction has been reported with welldefined molecular homogeneous catalysts only a few times. Such a catalyst must
perform several daunting tasks: it is responsible for breakingfour strong O-H
13 Huynh, MHV; Meyer, TJ. Chem. Rev., 2007, 107, 11, 5004-64.
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bonds (of bond dissociation enthalpy 119 kcal mol-1), and it must de-align spins to
form triplet 302 from spin-paired H2 0. Additionally, the intermediates involved are
normally so reactive, that auto-oxidation of the catalyst often leads to degradation
and inactivation - so the catalyst must be unusually robust or be capable to repair
itself.14 The first such solution-based ex vivo example, reported by Meyer and
coworkers, is a (bpy) 2(H20)Ru"'-ORu'(OH2)(bpy)2 [(bpy) = 2,2'-bipyridine]
complex that employs cerium (IV)oxide as the oxidant.1 516,17 The spectroscopic and
18
magnetic evidence of the high-valent Ruthenium(V)-oxo specie in Meyer's catalyst
has served as positive attestation for the existence of a radical mechanism passing
through two high-valent metal-oxo centers. Several investigators have derivitized
Meyer's strategy, and made modest-to-impressive improvements of the system by
using molecular scaffolds in order to pre-arrange high-valent Ru oxos to predispose
their reactivity to 0-0 bond formation. 19
Effective water splitting catalysts could have a variety of interesting
applications. In conjunction with fuel cells, commercial electrolyzers en masse
could play a role in solar energy storage by helping to overcome the diurnal cycle.
W; Yagi, M; Wolf, K; Bernasek, S; Dismukes GC. J.Am. Chem Soc., 2000,
122, 10353-57.
15 Gersten, SW; Samuels, GJ; Meyer, TJ.]. Am. Chem. Soc., 1982, 104, 4029-4030.
16 Geselowitz, D; Gersten, DJ; Meyer, TJ.]. Am. Chem. Soc., 1985, 107, 3855.
17 Geselowitz, D; Meyer, TJ. Inorg. Chem., 1990, 29, 3894.
18 (a) Binstead RA, Chronister CW, Ni J,Hartshorn CM, Meyer TJ.]. Am. Chem. Soc.,
2000, 122, 8464-8473. See recent work on this question: Cape, JL; Lymar, SV;
Lightbody T; Hurst, JK. Inorg. Chem., 2009, in print.
19 (a) Naruta, Y; Sasayama, M; Sasaki, T. Angew. Chem., Int. Ed., 1994, 33, 1839-41.
(b) Limburg, J; Brudvig, GW; Crabtree, RH. ].Am. Chem. Soc., 1997, 119, 2761-62.
(c) Zong, R; Thummel, RP. ].Am. Chem. Soc., 2005, 127, 12802-3. See also, (d) Wada,
T; Tsuge, K; Tanaka, K. Angew. Chem. Int.Ed., 2000, 39, 8, 1479-82.
14 Ruettinger,
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In such a paradigm, excess electricity generated by photovoltaics during the day
would be used to generate hydrogen gas, which in turn could subsequently be fed
through fuel cycles at night to re-generate electricity. Secondly, if hydrogen
becomes an important fuel source in other utilizations, such as the transportation
sector, effective electrolyzers will be in high demand.
Catalysis of the formation and cleavage of 0-0 bonds, trapping and
liberating the energy in either process, is a scientific matter of immense
fundamental import whose elucidation invites a large number of applications in
energy technology. Two issues pertinent to 0-0 bond are discussed further in this
thesis. In the first chapter (Section II), a model catalytic system called the Hangman
porphyrin is presented. The Hangman, reported originally by Nocera and
coworkers in 2002, is a chemical device that facilitates 0-0 bond formation and
bond cleavage by coupling redox events to proton transfer. The relevance of proton
transfer in catalytic redox pathways will be discussed at length. Results obtained by
my research efforts clarify the balance between redox events and bimolecular
substrate transfer in the dismutation of H20 2.
A second chapter (Section III) concerns an organicconstruct that was
designed to effect 0-0 bond formation using electrochemically derived radical
species. The effort investigates the role molecular geometry and frontier orbital
contributions has on electrochemical properties of interest for 0-0 bond formation
or water oxidation.
The results of Section II are primarily drawn from published work in
Rosenthal, Chng, Fried, and Nocera - see reference 28. Some preliminary results of
-13-
Section III were reported in Fried, Kanan, and Nocera (see reference 46) in The
Nucleus, the publication of the northeast section of the American Chemical Society.
Most of the results relevant for discussion however are prior unpublished, and are
presented herein for the first time in print.
-14-
II. H20z Dismutation by "Hangman"-PorphyrinArtificial
Catalases.
2005 to 2006
Introduction.
Oxygen activation by heme-Iron centers is exploited by Nature for cellular
energetics.20 Oxygen is a small molecule, and like many small-molecules demands
Asp
0O
H
H
His
His
N
N--.H
,, H
NH
2
NO
HO
H
H
-H,
Thr-
-
O/
-
(a)
(b)
(e)
Figure 1. Comparisons of proton-activated 0-0 bond cleavage in (a) peroxidases, (b)
catalases, and (c) cytochrome P450 monooxygenases. Several commonalities include the ironporphyrin heme group being employed as an electron transfer platform, in conjunction with
proton-donating functional groups in the secondary coordination sphere. Figure adapted from
reference 20a.
(a) Hoganson, CW; Pressler, MA; Proshlyakov, DA; Babcock GT. Biochim. Biophys.
Acta, 1998, 1365, 170-4. (b) Schultz, BE; Chan, SI. Ann. Rev. Biophys. Biomol. Struct,
2001, 30, 23-65. (c) Kadenbach, B. Biochim. Biophys.Acta, 2003, 1604, 77-94.
20
15-
the coupled transport of electrons and protons in order to activate it for further
reactivity or to effectively release energy from its reduction. Through the targeted
use of select amino acid side chains, whose acidic or basic functional groups sit
within the secondary coordination sphere of a metal-coordination complex, proteins
such as catalase and cytochrome c react with H202 and 02 to generate reactive Ironoxo species in their active sites. 3 The use of a "distal" proton source/sink provides
kinetic control of proton transfer, and therefore bond polarization, prior to 0-0
21
bond cleavage; this phenomenon has traditionally been labeled the pull effect.
(B)
Scheme 2 outlines
various interactions
+
between an Iron
02
(A)
(C)
fT
S+
F
20 coordination
(D)
i
porphyrin and
molecular oxygen
OH
Scheme 2. Representative iron-oxygen transformations found in
biological systems.
frequently found in
enzyme chemistry. Reversible 02 binding, which results in a putative Iron(III)
superoxo (complex B in Scheme 2) is representative of the interaction that a noncatalytic porphyrin performs for oxygen-transport, such as in hemoglobin and
myoglobin. Alternatively, an Iron porphyrin associated with redox-active
functionality activates oxygen by formation of discrete Iron(III) hydroperoxide
species (complex C). Complex C-type intermediates are featured in Figure 1 in
various catalytic metalloporphyrin enzyme environments.
21 Sono, M; Roach, MP; Coulter, ED; Dawson, JH. Chem. Rev., 1996, 96, 2841-2887.
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In the example given by Figure Ic, a depiction is given for the further activation of
02 in a monooxygenase enzyme. The active site contains a metalloporphyrin to bind
the equivalent of 02, and additionally contains catalytically active aspartic acid and
threonine. 22 The iron-bound O is fated to become an iron-oxo for atom transfer,
whereas the distal 0 is effectively reduced to H20. The mechanism implicates the
localization of electrons, formerly covalent in the 0-0 peroxy (i.e., sigma) bond,
onto the distal 0. This electron transfer, otherwise difficult, is facilitated by the
hydrogen-bond the O-atom forms to threonine (polarizing it for reduction), followed
by protonation of the O-atom by threonine (preventing the formation of a discrete
charged specie). In cytochrome P450 monooxygenase, the split 0-0 bond's energy
is effectively collected by the formation of a high-valent iron-oxo porphyrin, and the
resulting ferryl (FeIV=O) functional group is poised for further reaction with external
substrates. 23 This structure is schematically represented by (D) in Scheme 2, socalled "Complex I" in bioinorganic literature. Complex I is a high-energy
intermediate, accessed in part by the activity in the secondary coordination
sphere, 24 as illustrated in the prior description. The distal side of the heme is crucial
for providing a microenvironment surrounding the open coordination sites for the
binding of molecular oxygen, and directing its transformation.5 The description of
this bond rearrangement in detail is suggestive of the role that proton transfer plays
in the conversion of 0-0 bonds.
Nicholls, P; Fita, I; Loewen, PC. Adv. Inorg. Chem., 2001, 51, 51-106.
See Ortiz de Montellano, PR. Cytochrome P450: Structure,Mechanism, and
Biochemistry,2nd ed.; Plenum: New York, 1995.
24 Green, MT; Dawson, JH; Gray, HB. Science, 2004, 304, 5677, 1653-6.
22
23
-17-
We sought to combine acid-base and redox functionalities onto a single
molecular platform that would, in a biomimetic fashion, enable an intramolecular
"shuttling" phenomenon of protons to the demand of charged intermediates that
form during the course of small-molecule redox pathways. To direct PCET toward
the metal coordination site of the small-molecule activation, we encountered a need
to target constructs where electron delivery and proton delivery occurred interfacially, schematically shown in Figure 2.
[BH]
facial strategy
I
I
H+
Z
M ,,
M
[BH]
A side-to-side PCET catalyst
inter-
H eThe
e
/
An inter-facial PCET catalyst
Figure 2. Schematic description of putative catalytic PCET devices
demands the use of
a spacer, which
holds an acid-base
functionality pending over the redox functional group. The choice of spacer
molecules, xanthene and dibenzofuran, was adopted based on studies on
diporphyrin xanthene (DPX) and dipophyrin dibenzofuran (DPD), constructs that
2 5 These spacers were
organize two redox cofactors along face-to-face geometries.
shown to display an extensive range of vertical pocket dimension between
macrocyclic subunits. Studies on synthetic cofacial porphyrin systems have enjoyed
(a) Chang, CJ; Deng, Y-Q; Heyduk, AF; Chang, CK; Nocera, DG. Inorg. Chem., 2000,
39, 959-66. (b) Deng, Y-Q; Chang, CJ; Nocera, DG.].Am. Chem. Soc, 2000, 122, 4101.
25
-18-
a long and productive history.26 However, systems that pair porphyrins (a redox
unit) with acid/base chemistry are comparatively newer. To furnish the new model
catalyst of interest, the prior "Pacman molecules" (DPX and DPD) are synthesized
instead with a proton donor group in place of one of the porphyrin subunits.
Reported originally in 2001, this "Hangman" model complex deploys a xanthene
spacer in order to "hang" an acidic proton over the redox-active metalloporphyrin
platform, 27 to mimic the characteristic features of enzymes that promote some of
the most challenging redox transformations.
Hangman molecules were reported to carry out the exothermic but
kinetically inert dismutation (also called disproportionation) of H202.5
catalase
2H 20 2
- 0 2 + 2H 2 0
(2)
Chang and coworkers determined that employing Iron(II) as the Hangman's
metal and a carboxylic acid as its pendant acid group (letting M=Fe and BH=COOH of
the schematic molecule of Figure 2) allowed for the most reactive catalyst, with
turnover numbers (TON) up to 436. The research showed that the Hangman
approach yields superior catalysts to analogues that do not manage both proton and
electron inventories simultaneously. However, initial work on these systems did
28
not address the influence of the redox potential of the porphyrin component itself.
In nature, heme refers to a large family of iron-containing metalloporphyrins that
(a) Collman, JP; Elliott, CM; Halbert TR; Tovrog BS. Proc.Nat'l.Acad. Sci. USA,
1977, 74, 18-22. (b) Durand Jr., RR; Bencosme, CS; Collman, JP. J.Am. Chem. Soc.,
1983, 105, 2710-8.
27 (a) Chang, CJ; Yeh, C-Y; Nocera DG. ]. Org. Chem., 2002, 67, 1403-06. (b) Yeh, C-Y;
Chang, CJ; Nocera, DG. J. Am. Chem. Soc., 2001, 123, 1513-14.
28 Rosenthal, J; Chng, LL; Fried, SD; Nocera, DG. Chem. Commun., 2007, 2642-4.
26
-19-
are decorated with a range of different functional groups on the pyrrole alpha and
beta sites - for example; protoporphyrin IXcontains 2 vinyl groups, and 2 propionic
acid groups, but heme c in cytochrome c contains 2 propionic acid groups and 2
CH(SH)(CH3) groups. 29
These groups undoubtedly influence the energy of the high-lying n-system
e
tBu
/
electrons and those of the
coordinated transition metal, and
\-COOH
tune the potential of the platform to
Ar
-
N
CI
- -I
lFe
A-
match the redox potentials of the
Ar
rN
target substrate. We expect such a
Ar
tBu
derivitization to be relevant to the
F
Ar =
catalytic chemistry of Hangman. In
Ar=
6a
F
6b
the present work, Hangman
oM
6e
porphyrins are modified by
Figure 3. Electronically disparate Hangmans.
functional groups that tune the
electron density, paralleling the diversity of the heme family, to test how these
properties affect the catalytic dismutation of H20 2. This modification is shown in
Figure 3, which provides structures to 6a-c, the synthetic targets of this study.
Electron withdrawing and donating groups positioned at the meso positions have
been previously shown to strongly influence the redox properties of the porphyrin
unit. For instance, the porphyrin/porphyrin'* couple in Zinc(II) porphyrins shifts
29 Yeh,
SR; Han, S; Rousseau, DL. Acc. Chem. Res., 1998, 31, 11, 727-35.
-20-
30
significantly along the series Ar = 2,6-dimethoxyphenyl (E = 0.71 V vs. NHE),
mesityl (E = 0.98 V),31 pentafluorophenyl (E = 1.20 V). 3 2 By accessing a similar
range of potentials in complexes 6a-c, and testing the catalytic behavior of each, we
seek to elucidate the electron-transfer half of the PCET-based dismutation of
hydrogen peroxide.
30 Seth, J; Palaniappan, V; Johnson, TE; Prathapan, S; Lindsey, JS; Bocian, DF.
J. Am.
Chem. Soc., 1994, 116, 10578-92.
31 Otsuki, J; Narita, T; Tsutsumida, K; Takatsuki, M; Kaneko, M. J. Phys. Chem. A,
2005, 109, 6128-34.
32 Sena, A; Krishnana, V.]. Chem. Soc., FaradayTrans., 1997, 93,4281-4288.
-21-
Results.
The strategy for the synthesis of porphyrin Hangman complexes is shown in
Scheme 3, and borrows heavily from the approaches described prior by Chang and
colleagues.5 ,25 A commercially-available xanthene dibromide is asymmetrically
functionalized by treating it with one equivalent of PhLi in DMF. An in situ aryl
aldehyde is protected as an acetal via acid-catalyzed condensation with the diol. 2,
in Scheme 2, is transformed into the aldehyde/carboxylic acid by quenching a
lithium-halogen exchange product in CO2 and performing an acidic work-up in
trifluoretic acetic acid, furnishing 3. Under standard acid-catalyzed esterification
conditions with H2 SO4, the carboxylic acid is protected, forming the
aldehyde/methyl ester product, 4. Porphyrin formation is performed under
standard Lindsey conditions to deliver a freebase porphyrin Hangman, 5. The
mesityl groups in the meso positions of the porphyrin found on 5a, prevent the
33
formation of bisiron(lI)-[t-dimers after metallation with Iron.
33 (a) Cheng, R; Latos-Grazynski, L; Balch AL. Inorg. Chem., 1982, 21, 2412-18. (b)
Calderwood, TS; Bruice, TC. Inorg. Chem., 1985, 25, 3722-24.
-22 -
B
A
1
2
3
tuu
aAr
COO
OMe
OC
D
F
0
b
F
MeO
H
tBu
tBu4
OMe
Sa-c
Scheme 3. Synthesis of 5a-c. (A): (i) 1 equiv PhLi, C6H 12/THF solv.; (ii) DMF xs., H2 0; (iii)
Neopentyl Glycol, PhO-SO20H (cat.), A. (B): (i) 1 equiv PhLi, C6 H12/THF solv.; (ii) CO2; (iii)
TfOH (cat.), H2 0. (C): MeOH solv., H2 SO4 (cat.), A. (D): (i) pyrrole, aryl aldehyde (Ar-CHO),
BF 3-OEt 2, CHC13 solv.; (ii) DDQ; (iii) AcOH, H2 SO 4, H20, A.
In the present study, the aim of the research is to study to what extent
catalytic efficacy of the Hangman depends on the stereoelectronic properties of the
redox-active porphyrin unit. Previous work has demonstrated that the pKa of the
pendant acid group dramatically affects the ability of PCET to take place and
therefore catalyze H2 0 2 dismutation, and that maximal PCET is attained when the
carboxylic acid functional group is used. Porphyrin formation in this synthetic step
requires that 4 react with a variety of different aryl aldehydes and pyrroles in order
to generate Hangmans with electronically disparate porphyrins, 5a-c. The synthesis
-23-
of the freebase porphyrin is concluded by acid-catalyzed hydrolysis of the ester to
the desired carboxylic acid group on the upper "cleft" of the Hangman.
The crystal structure of the freebase porphyrin is shown in Figure 4.
Although
similar in
principle to
other Hangman
derivatives, 25
several
O
noteworthy
structural
features include
the relative
Figure 4. Crystal structure of 5c, the freebase precursor to 6c. Thermal
ellipsoids given at the 50% probability level. Crystal structure obtained by
L.L. Chng, see reference 28.
geometry of the
xanthene plane,
which is canted 780 with respect to the porphyrin plane. Also, the sp3 hybridized
carbon in the xanthene pillar causes the aromatic backbone to bend by nearly 150.19
Similar distortions have been reported in xanthene-porphyrin arhcitectures.3 4 The
2
freebase porphyrins were metallated with FeBr2, giving rise to the 3 porphyrin-Fe +
catalysts, 6a-c, shown in Figure 4.
34
Chang, CK; Bag, N; Guo, B; Peng, SM. Inorg. Chim. Acta., 2003, 351, 261-68.
-24 -
The hydrogen peroxide dismutation studies were performed at room
temperature in a septum-sealed 10 mL reaction vial equipped with a magnetic
stirbar and a capillary gas delivery tube linked to a graduated burette filled with
water. The reaction vial was charged with 1 jtmol of the Iron porphyrin catalyst, 25
tmol of 1,5-dicyclohexylimidazole, 1.5 mL of CH2C12 and 0.5 mL of CH3OH. The
solution was stirred for 5-10m beforehand to guarantee gas pressure equilibration
and solution homogeneity. Then, an aliquot of 10.4M (30% v/v) H2 02 (110 L) was
added to the reaction mixture via syringe through the septum, and the reaction
mixture was allowed to continue to stir vigorously. The time was set to zero
immediately after addition of H202. The conversion of the reaction was monitored
volumetrically (i.e., by the displacement of water in the burette with bubbles of 02
evolved), and the turnover number (TON) for 02 produced was calculated by the
ideal gas equation, pV = NkBT, letting p = 1 atm = 101,300 Pa. The identity of the
oxygen gas was
Table 1. Reactivity data for H2 0 2 dismutation
confirmed
FeCI(TMP)
0.2 ± 0.1
162 ± 14, 30%
independently by the
FeCl(TMP) + 1 equiv.
2.4 ± 0.4
236 ± 16, 44%
alkaline pyrogallol test.
6a
102.3 ± 5.3
533 ± 8, 98%
6b
22.3 ± 1.3
160 ± 15, 31%
6c
27.2 ± 1.4
147 ± 6, 27%
PhCOOH
Turnover frequency (TOF) recorded over initial 30 seconds of
reaction. TON given after 60 minutes of reaction.
The catalytic
reactivity data for H2 02
dismutation is given in
Table 1, along with two control experiments of non-Hangman tetramesityl
-25-
porphyrin-Fe 3+ (TMP = tetramesityl porphyrin) test catalysts. The control
experiments afford the possibility of determining the role of the "Hangman" effect
by comparing the effect of an electron-only catalyst (the porphyrins) with a PCETbased system that provides proton shuttling concomitant with electron transfer.
The mesityl-Hangman, 6a, was the most robust catalyst; on average, each
molecule of 6a dismutated 533 equivalent of H 2 0 2 , resulting in 98% of the original
H20 2 Sample becoming reacted. The initial rate, as determined by the first minute of
reaction, is given as a turnover frequency (TOF) in min -', and was also the highest
for 6a by a significant margin (102.3 min-1). The other two Hangmans, 6b and 6c,
had strikingly similar overall and initial behavior (TON - 150, TOF - 25 min-1): fast
turnover initially (although not as fast as 6a), and quick deactivation.® In the
control cases, where redox-active porphyrins lacked an intramolecular proton
source/sink, reactivity was sluggish but proceeded over nearly the full one-hour
duration.
0 Time course plots are available in the Supplementary Information section, IV-2.
-26-
Discussion.
As shown in Table 1, the most effective catalyst studied was 6a, which
converted essentially all H202 present in the vial within the first five minutes of
reaction.
The high activity of 6a in marked contrast to the non-Hangman tetramesityl
porphyrins is representative of the artificial "pull effect" induced by intramolecular
proton delivery. Although the addition of benzoic acid, providing an external proton
source, has some effect in accelerating the reactivity, the use of an internal proton
source has a preeminent role in maximizing the catalytic strength of the Iron
metalloporphyrin. Interestingly, the electronic functionalized porphyrin systems
did not strongly vary in their catalytic behavior, with comparable initial and overall
turnover data (see Table 1); notwithstanding the well-attested discrepancy between
the oxidation potentials conferred by the functional groups used, as discussed prior.
Nevertheless, the present data
H
o
oe
+07
Ashow
t]ok
\-0.
0
/
o.. O.
minimal difference
between the two electronically
most disparate species (6b
and 6c), and the greatest
efficacy in the intermediate
Scheme 4. PCET-based catalytic cycle of H2 0 2 dismutation
mesityl-derivative, 6a. The
most likely explanation of this behavior is the possibility of an inactivation pathway
through I-oxo dimerization, as shown off to the left in the putative catalytic cycle of
-27-
Scheme 4. A convoluting variable, steric bulk plays a large role in the catalyst
stability because Iron porphyrins in solution are susceptible to equilibrate toward a
thermodynamic Fe"'-O-Fe"l type-structure. 35 However this dimerization process is
prevented by the large van der Waals radius of the mesityl group, explaining the
robust catalyst lifetime of 6a and the two TMP controls. Indeed, mesityl-apended
porphyrins are one of only a few cases in which a monomeric Iron (III) hydroxide
porphyrin system can be isolated. 32a Inactivation by dimerization stops the catalyst
cycle at transformation A (see Scheme 3), by preventing the exchange between
water and hydrogen peroxide (in the form of hydroxide and hydroperoxide ligands).
Whereas HO- displacement by HO2 - is facile because of the peroxide's greater
acidity and stronger coordination, HO2 - apparently does not readily interact with
the low-energy Fe"'-O-Fe"l bridge.
Consistent with prior models, we implicate the existence of a high-valent
ferryl-oxo/porphyrin radical-cation intermediate, which forms in transformation B.
Here, proton-coupled 0-0 bond scission releases an H2 0 equivalent by extracting
two electrons from the metalloporphyrin system - one from Fe, and the second from
the a-system. The resulting transient Iron(IV) species is highly oxidizing and is
involved in the subsequent 02 formation step.
The lack of steric bulk in 6b and 6c accounts for their speedy inactivation, as
evinced by the fact their overall TON is comparable to the non-Hangman controls,
yet their initial activity is substantially higher. Before dimerization occurs, the
3s (a) Chang,CJ; Loh, ZH; Shi, C; Anson, FC; Nocera, DG. J.Am. Chem. Soc., 2004, 126,
10013-20. (b) Jayaraj, K; Gold, A; Toney, GE; Helms, JH; Hatfield, WE. Inorg. Chem.,
1986, 25, 3516-18.
-28-
Hangman structure nevertheless induces catalysis; in contrast, control studies
conducted under the same conditions employing non-Hangman pentafluorophenyl
and 2,5-dimethoxylphenyl meso derivatives of Iron(III) porphyrin resulted in
negligible oxygen evolution, indicating that in these cases dimerization (shown
previously to occur in these systems 3 5b) completely obviates catalysis.
The present interpretation facilitates an understanding of: (1) the role of
meso mesityl groups to safeguard from inactivation, and (2) the importance of an
intramolecular Bronsted-Lowry acid/base group. The role of redox potential of the
3 32
porphyrin, varying possibly by as much as 490 mV 0- must also be examined. The
present data show that the disparate potentials are not reflected in a pattern of
catalytic activity, as shown in Table 1. In fact, time course data for the 2,5dimethoxyphenyl and pentafluorophenyl structures were the most similar to one
another of any the reactions studied. This result comes unexpected since the Iron
(III) porphyrin platform serves collectively as a two-electron donor in
transformation B and as a two-electron acceptor in transformation D in the putative
catalytic cycle. One interpretation of this result, operating within the framework
provided by Scheme 4, is the hypothesis that neither transformations B or D is ratelimiting in the catalytic cycle, implying that either A, C, or both are the ratedetermining steps. In transformations A and C, the catalyst is encountering a new
molecule of hydrogen peroxide, whose fate is either reduction to water or oxidation
to dioxygen, respectively. Accordingly, the data suggest that the catalyst - while
active - is limited most by the elementary steps that are bimolecular,that is, the
ones that require uptake of new substrate. This observation is in agreement with
-29-
36
the fact that catalases are some of the fastest enzymes known, with kcat values
approaching the diffusion limit. Although not replicating the reaction velocity of
catalases, our data sugggest that the PCET feature of the Hangman molecule
captures the fundamental chemistry that permits catalase to operate toward the
diffusion limit.
Incapable of producing water-splitting activity, the Hangman molecule
provides an important insight in the fundamental science of 0-0
bonds, and the
role that intramolecular proton shuttling plays in catalyzing these events. There
also emerges an intriguing and unexpected negative result, that redox potentials
appear not to be the most critical feature of the catalyst's structure. In the following
section, we focus on molecular geometry, and the constraints it imposes on 0-0
bond processes.
36
Job, D; Jones, P; Dunford, HB. ]. Phys. Chem., 1993, 97, 36, 9259-62.
-30-
III. Studies Toward an Organic 0-0 Bond Forming
Catalyst via Bisindole Carboxylates.
2006 to 2008
Introduction.
The ruthenium "blue dimer" complex (shown in Figure 5L) is the first and the
most studied molecular water-splitting catalysts.3 Nonetheless, complex 5L and
-
those derived from it
N
OH
N
NI
and over-potentials;
Ru---R u-N
H20 I
HN'
N
-
Ru-N
[ -J
[Ru(bpy)20H220
(L)
have modest turn-over
N-Ru-N
/
Xan[(tpy)Ru(bpy)OH2]2
(R)
the former limitation
owing mostly to their
low lifetime,3 8 and the
Figure 5. Two ruthenium-based water-oxidizing catalysts
latter representing
deficiencies in kinetics. Previous work in the Nocera group at MIT has sought to
capitalize on the power of scaffolded di-nuclear complexes to drive formation of 037 Yagi, M; Kaneko, M. Chem. Rev., 2001, 101, 21-35.
38 Zong, R; Thummel, RP.J. Am. Chem. Soc., 2007, 127, 37, 12802-3.
-31-
O bonds by pre-arranging metal-oxos with the right geometry to react - this concept
underlies the "Pacman" molecules reported previously. In the "Pacman" approach,
39,40
serves to allow
the employment of a dibenzofuran or dibenzoxanthene spacer
flexibility of the metal nuclei to cross over a 4 A pivot range 41 - by so doing, the
structure can uptake new substrate and release products easily. In structure (R) of
Figure 5, the reactivity of Ru"' pyridines is combined with geometric control
afforded by cofacial architecture.
The ancillary ligands impose metal-oxo vectors to be approximately
collinear, auspiciously directing oxygen-based reactivity to a twin coupling partner.
The two (bpy)-coordinated Ru" species of 5R behave initially as electronically
isolated systems; several oxidation events later, a large catalytic wave in the cyclic
voltammogram around 1.7 V vs. NHE signals irreversible processes involving a
[Rulv(O)]
2
specie evolves molecular oxygen, demonstrating that catalysis of 0-0
bond formation is enhanced by structural considerations. 42 Similar observations
were made by Thummel and coworkers: preparation of bis-tridentate ligands
capable of holding ruthenium cores in well-defined orientations with respect to one
another resulted in overall oxygen evolution at turnovers significantly higher than
38
those originally reported by Meyer under the same oxidizing conditions.
(a) Loh, Z-H; Miller, SE; Chang, CJ; Carpenter, SD; Nocera, DG. J.Phys. Chem. A,
2002, 106, 11700-9. (b) Chang, CJ; Loh, Z-H; Deng, Y-q; Nocera, DG. Inorg. Chem.,
2003, 42, 8262-9.
40 Rosenthal, J; Nocera, DG. Acc. Chem. Res., 2007, 40, 543-553.
41 Deng Y, Chang VJ, Nocera DG.]. Am. Chem. Soc., 2000, 122, 410-11.
42 Betley, TA; Wu, Q; Van Voorhis, T; Nocera, DG. Inorg. Chem., 2008, 47, 1849-1861.
39
-32-
If an intramolecular oxygen atom coupling step is important (and every
mechanism contrived for the blue dimer complex implicates one4 3 ), then the
structural features of the blue dimer are far from conducive toward the most
straightforward reaction path. 5L competently oxidizes water only by driving the
reaction with the chemical oxidant, ceric ammonium nitrate ((NH4)2 CeIV(N0 3)6, Eox
- 1.7 Vvs. NHE), vastly more oxidizing than water is reducing. It has been
estimated that rotation about the I-oxo bond to yield an eclipsed geometry between
Ru-0 bonds in 5L still places 0 atoms 3.2 Aapart, 44 far greater than a standard
peroxy bond length of -1.5
A. If 0-0 bonding is rate determining, as has been
supposed, 37 one reason for the blue dimer's lackluster energetic profile could be the
awkward gymnastics it must perform to reach certain key intermediates.
The present work concerns a novel strategy to water oxidation by noting
several themes developed by inorganic chemistry. The role of ruthenium in the blue
dimer catalyst, in a general sense, is to assist in the production of an intermediate
that has valence orbitals of oxygenic character. However, organic systems are also
capable of establishing oxygen-centered reactivity. For example, studies on the
benzoyloxy radical hyperfine structure by electron paramagnetic resonance (EPR)
spectroscopy reveal that the spin density resides nearly entirely on the two oxygen
atoms,45n implying that the "left" resonance contributor in Figure 6 is the more
43 Yang, Y; Baik, M-H.]. Am. Chem. Soc., 2008, 130, 48, 16231-40.
44 Gilbert, JA; Eggleston, DS; Murphy, WR; Geselowitz, DA; Meyer, TJ. J.Am. Chem.
Soc., 1985, 107, 3855-64.
45 McBride, JM; Merrill, RA.]. Am. Chem. Soc., 1980, 102, 1723.
-33-
dominant. The hyperfine structure of organic carboxyl radicals is a basic result
potentially of interest to the chemistry of 0-0 bond formation.
In one mechanism
O0
o1+
O
proposed for 02 evolution from
-
metal-oxo catalysts such as the
ruthenium dimer system (Figure
Figure 6. Resonance of benzovloxv radical
5L), 0-0 bonds form from two orbitals of M-O n*character. These orbitals are
respectively the single-occupied molecular orbitals (SOMOs) of the corresponding
metal-oxo complexes. This mechanism is sketched in Figure 7A. In the lower half of
[Mn+2"
(A)
Q
figure 7, (B),
2[Mn] + 02
o =Mn+2
a radical
(B)
Rred
0
RRox
O
Rred -
+02
Figure 7. Radical coupling for 0-0 bond formation. (A) shows coupling between
n
netal-oxos; (B) shows a putative organic equivalent.
cupling
pathway
employing
organic
radicals is shown. The reactivity to form 0-0 bonds from the left-hand side of the
arrow is provided by oxygen-centered carboxyl radicals; the ability to further evolve
oxygen from the benzoyl peroxide-type intermediate would require a coupled
functional group in an oxidized state to become reduced (the role that is played by
the transition metal in 7A).
1 "INDO predicts spin density of 0.54 on each oxygen, -0.10 on the carbonyl carbon,
and <0.01 on every other atom of 2B2 benxoyloxy." (from reference 45)
-34-
Figure 7B invites a program for studying 0-0 bond formation that has not
received wide inquiry in the water-splitting literature. 46 Firstly, we ask whether
organic molecules provide an orbital manifold to stabilize oxygen-centered
reactivity. The result obtained by McBridge suggests aryl carboxylic acids indeed
deliver such a possibility. Once oxygen centered radicals are obtained, a catalyst
must focus this intermediate toward productive 0-0 bond formation. With
reference to metal-oxo systems, the application of a dimeric species appears to be a
crucial component at this juncture.
0-0 bond forming events in the Meyer ruthenium complex1 8 ,43 as well as in
the natural photosynthetic oxygen-evolving center (OEC) of photosystem II6,47
implicate dimeric-structures that symmetrically interface two copies of a given
catalytic machinery to form dioxygen. Therefore, in pursuing the chemistry
illustrated by 7B, we will be most interested in organic aryl carboxylic acid dimers in
0
order to favor intramolecular reactivity.
OH
Finally, ruthenium catalysts
o
HO
,-
demonstrate the importance of structural
rigidity and the pre-arrangement of oxygen
Sn-i
atoms to alleviate the entropic costs of 0-0
Figure 8. 2,2'-bisindolyl-N,N'-alkylated-
3,3'-dicarboxylic acids
bond-forming transition states (from the
discussion comparing complex 5L and 5R). This aspect, which we label
"stereocatalysis" (catalysis accessed through particular spatial orientation), is
Fried, SD; Kanan, MW; Nocera, DG. The Nucleus, 2008, 86, 9, 14-20.
47 Brudvig, GW; Crabtree, RH. Proc. Natl. Acad. Sci. U.S.A., 1986, 83, 4586-4588.
46
-35-
explored in depth in the context of organic constructs. Synthetic organic chemistry
opens avenues to prepare highly conformationally-restricted molecules. A
stereocatalyst profits from such restrictions, using them to enforce certain (desired)
reaction pathways and prohibit others by virtue of its molecular geometry. In this
context, it must rigidly place two oxygen atoms (and upon oxidation, two oxygen
radicals) in proximity to one another in order to facilitate 0-0 bond formation. In
this work, we investigate the structural properties of the class of synthetic targets
shown in Figure 8 toward this end. 46
-36-
Monomer Results.
Two criteria need to be demonstrated to provide a case for the utility of
organic systems in 0-0 bond formation catalysis. One inquiry pertains to the
nature of the radical formed by one electron oxidation of an aryl carboxylic acid;
secondly the geometric features of the bridged dimer motif shown in Figure 8 must
be assessed. The former criterion is analyzed using monomeric aryl carboxylic
acids. The choice to focus on indoles rather than benzenes is motivated by the fact
that n-rich arenes (such as indoles and pyrroles) are more prone to oxidation than
8
the associated benzenes.4
49
Radical structure was investigated by density functional theory (DFT)
calculations and electrochemical measurements by differential pulse voltammetry
(DPV). DFT-simulated highest occupied molecular orbitals (HOMO) indicate that
spin density is O-atom centered in the anionic forms, as shown in Figure 9.
J
(A)
1
40
.0
(C)
(B)
(D)
Figure 9. DFT structures of N-methyl indole 3-carboxylic acid HOMOs. (A): 1-methyl-1Hindole-3-carboxylic acid. (B): 5-methoxy-1-methyl-1H-indole-3-carboxylic acid. (C): 1-methyl1H-indole-3-carboxylate. (D): 5-methoxy-1-methyl-1H-indole-3-carboxylate.
Kettle, LJ; Bates, SP; Mount, AR. Phys. Chem. Chem. Phys., 2000, 2, 195-201.
49 DFT calculations were conducted by Sebastian Stoian. They were conducted
using a standard Gaussian package with a B3LYP/6-311G basis.
48
-37-
In carboxylic acids (A) and (B), the highest-lying electrons are n-delocalized.
However (C)and (D), indole carboxylates, have HOMO electron density almost
entirely on the oxygen atoms. Further DFT studies on indole carboxyl radicals (the
singly-oxidized indole carboxylate species) show that spin density is oxygenic,
which is consistent with the EPR data of the benzoyloxy radical. This spin
distribution would be essential for a radical coupling strategy in 0-0 bond
formation. Addition of an electron-donating methoxy group to the indole carboxylic
acid at the 5-position (structure 9B) results in a contribution to the HOMO,
suggesting that substitution of the indole ring provides a means to modulate the
redox potential of the system. The calculations do not predict contribution of a 5methoxy group to the frontier orbital in the anionic case (compare orbitals of 9C and
COO0
COOH
COOH
COOE
\Meo
MJo
9D).
Oxidation
potentials of the
monomer species are
I
/given
in Figure 10. Note
that all oxidation
14648mV
I '
148 mV
'
potentials observed and
\I
888 rnV
reported are "halfwave"
I
potentials, E , rather
s91 mV
1600
1400
2zoo 1000o
ao
6oo
400
than true oxidation
mV (vs Ag/AgCI)
Figure 10. DPV of indole carboxylic acids and carboxylates.
Studies of carboxylic acids conducted in DMF; of carboxylates in
0.1 M KP, water pH=7.0; on a glassy carbon electrode.
-38-
potentials, Eox, since the
oxidations were irreversible in all cases. Although halfwave potentials are not
equivalent to true redox potentials, comparisons between them are nonetheless
diagnostic of electrochemical behavior.
Species possessing the n-donor methoxy functional group are -110 mV
easier to oxidize than their counterparts, demonstrating redox tunability of the
indole carboxyl system by such substitution. Of note is that addition of 5-methoxy
to 1-methyl-1H-indole-3-carboxylate lowers the oxidation potential similarly to in
1-methyl-1H-indole-3-carboxylic acid, in contradistinction to the DFT calculation for
struture 9D.
The anions undergo markedly more facile oxidations, by nearly half a volt,
demonstrating the accessibility of organic radical species under aqueous conditions,
in the same general energy range of many transition metal redox events. That
ionization facilitates oxidation so much more than placing an electron-donor group
on the aryl moiety suggests oxygenic center to the radicals formed from (5methoxy-)1-methyl-1H-indole-3-carboxylate (as alluded also by the DFT
calculations). All the same, the aryl support ostensibly stabilizes these radicals
substantially - noting that the one-electron oxidation potential of acetic acid and
acetate is significantly more difficult to access; the transformation cannot be readily
performed under laboratory electrochemical conditions, and is industrially carried
out at Pt anodes at highly elevated temperatures and pressures in the Kolbe-Schmitt
process.5 0 The result that an indole carboxyl is an O-centered radical but is
50 Lindsey, AS; Jeskey, H. Chem. Rev., 1957, 57, 4, 583-620.
-39-
nevertheless stabilized by the indole moiety is of interest for electrochemical
catalysis, as discussed in the introductory remarks.
-40-
Bridged Bisindoles Results.
Study of indole carboxylate monomers shows that oxygen-centered radicals
can be furnished electrochemically at potentials comparable to inorganic molecules.
The next effort is concerned with a putative structure that upon oxidation, localizes
two oxygen-centered radicals in proximity to one another in order to harness the
energy of carboxyl radicals toward intramolecular productive 0-0 bond formation.
Aproposal for a simple, geometrically-tunable, dimeric species that satisfies this
requirement is a bridged (i.e., N,N'-alkylated) bisindole, whose preparation is
summarized in Scheme 5. Alkylation conditions between methyl indole-3-
0
0
0
2.00 equiv nBuLI / THF
1.01equiv NaH, DMF
x
(1.
x
-sa
2.00 equiv CuCl, -780C
= I, Br, Ots
X
n1) 2,3,4
n
equiv
NN
N
25%-65%
(2a-.) a: n2
b: n=3
n-I
a 2
(3a.c) b: n-3
c: n=4
c: n=4
0
5:1 DMSO / 3MKOH
a: n=2
(4ac) b: n=3
Scheme 5. Synthesis of 4a-c
carboxylate (1)t and diterminal alkylene ditosylates or dihalides were optimized
such that for 2-, 3-, and 4- carbon linkers, isolated yields were obtained between 9095%. Complete synthesis descriptions are available in the supplementary
t For later studies, it was useful to consider a methoxylated derivative of 4b. The
synthesis commences with methyl 5-methoxy-1H-indole-3-carboxylate in place of 1,
and follows the same set of transformations (see IV-4). Methoxylated forms of 2-4b
are labeled with a "prime," id est, 2-4b'. The product is labeled 4b'.
-41-
information section IV-4. The second step of the procedure proved to be the most
difficult of the synthesis. To form the 2,2'-indolyl bond, a methodology involving
directed metallation and oxidative coupling via an inorganic oxidant was developed.
Although other methods of indole-indole coupling are available,51 we chose this
method because it does not require prior functionalization at the 2-sites,5 2 and
therefore allows for a much-desired three-step synthesis.v Oxidative coupling
transforms 2a-c to 3a-c with moderate efficacy. Yields were often limited by the
compound's incomplete solubility in nBuLi-compatible solvents, and we generally
observed the trend that oxidative coupling was more effective with smaller linker
chains. It may be advanced that introducing more methylene units allows the
system more degrees of freedom, and therefore makes the desired C-C bondforming transition state more entropically disfavored. The final hydrolysis step
readily furnishes the di-carboxylic acid derivatives, 4a-c.
Compounds 4 were found to be only soluble in polar organic solvents, and
electrochemical studies later demanded (vide infra) a water-soluble variant. The
strategy of the modified synthesis to form a water-soluble derivative was to
generate a site on the alkyl-linker for phosphorylation (see Scheme 6).
Commercially available 1,3-dibromo propan-2-ol was protected with the t-butyl-
(a) Prieto, M; Zurita, E; Giralt, E.]. Org. Chem., 2004, 69, 6812. (b) Merlic, CA; You,
Y; Deng, Q.Tetrahedron,2001, 57, 24, 5199.
52 Benincori, T; Piccolo, 0; Rizzo, S; Sannicol6, F. ].Org. Chem., 2000, 65, 8340.
V The oxidative coupling strategy for the four-carbon bridged compound, 3c, was
suboptimal; instead 3c was prepared for future studies using standard Ullmann
coupling. See Supporting Information IV-4 for details.
51
-42-
dimethylsilyl group (TBDMS) in order to generate an "alcohol" equivalent that could
be carried through the harshly basic conditions of alkylation and nBuLi-promoted
coupling. Protection was easily performed,53 generating a precursor in 91% yield to
enter the alkylation route that had been used in previous syntheses. Of note is the
pleasing result that oxidative coupling proceeded in 65% yield, one of the highest
yields obtained.
1.25 equiv TBDMS-CI
r
25 equiv Imideok
24h/ 91%
Br
r
OTBDMS
OH
O
0
0\
1.01 equiv NaH
R
CH(TDM
0.0o equiv
95
R
m
0
I
I
equiv nBuL THF R
2
N
(1): R-H
(1'): R=MeO
equivCuCI,
65%N
R
0
(BN)
(BuN)-
N
R
OTBOS
OTBDMS
(2w')
[21 H2 0
94%
(4w)
(4w')
100%
(Sw)
(Sw')
(6w)
(6w')
Scheme 6. Synthesis of 6w and 6w'
s3 Axenrod, T; Watnick,C; Yazdekhasti, H; Dave, PR.]. Org. Chem., 1995, 60, 1959-64.
-43-
This result is consistent with the hypothesis that the limiting factor to the
synthetic viability of coupling is the solubility of the compound in THF. The addition
of the hydrophobic TBDMS group was observed to aid the solvation of the complex.
Subsequently, 4w and 4w' - the de-protected equivalent - was prepared by
reacting the coupled product, 3w('), with 3 equivalents of tetrabutylammonium
fluoride. Phosphorylated products were accessible in high yield by treatment of
reagents with excess POC13 and pyridine, followed by hydrolysis of remaining P-Cl
bonds via addition of acidic water to the reaction medium. Hydrolysis in 5:1 DMSO:
3 MKOH furnished the final target, 6w('), in quantitative yield. Figure 11 presents a
mechanical model and a region of the 1H NMR spectrum of the isolated 6w'
compound. In the downfield
*aryl
4V*A.
;
region, the spectrum
4
possesses two multiplets at
8=7.64 ppm and 6=7.00 ppm
corresponding to the six
--.. k
Figure 11. Part of the 1H NMR spectrum of 6w'
protons on the indoles' 4-, 6-,
and 7-positions. A tall narrow
singlet peak at 3.83 ppm is readily identifiable as the protons in the methoxy groups,
located at the indoles' 5-positions. The remaining five peaks in the spectrum
correspond to the non-degenerate protons of the bridging propyl group.
-44-
Detailed analysis of the structure of the bridged bisindoles, 4a-c, was
conducted in the solution and crystalline state. Single crystals of 4a-c and a nonbridged control (4) were obtained over the course of 4-8 days via vapor diffusion of
diethyl ether into dimethyl formamide (DMF) solutions of the compouds. 5 4 The
structures and relevant figures of merit are given in Table 2. The structures display
an increase in the dihedral angle between the indole-indole planes with respect to
the 2-2' indolyl bond, with an increase in the length of the alkyl bridge demonstrating that bridge length is a parameter that provides control of the overall
geometry of the structure. Unsurprisingly, the absence of a linking alkyl group
between the two indoles results in a dimer with free rotation around the 2-2' indolyl
bond, making the dihedral angle an arbitrary parameter, although a value of 113.90
based on the crystalline structure is reported. However, the two-carbon bridged
molecule, 4a, was also found to exercise free flexibility to dihedral rotation.
Minimal 0-0 distances across the two carboxylic acid groups were
calculated for complexes 4b and 4c by allowing rotation about the C-COOH bond in
structural simulation. Based on its approximate similarity to the bond length in
hydrogen peroxide (of 1.5
A), the three-carbon bridged bisindole carboxylic
acid is
predicted to be most appropriate for effecting 0-0 bond formation.
54 Crystallography and structure refinement was conducted by Dr. Peter Miller.
-45-
Table 2. Crystal structure data of compounds 4, 4a-c.
4
(no bridge)
4a
(2C bridge)
B
A'
(113.90)
N/A
19.00
N/A
59.80
1.60 A
68.8
2.09 A
4b
(3C bridge)
c~
-
4c
(4C bridge)
*In complexes where dihedral rotation is free about the 2-2' indolyl bond, rigid 0-0 atom
distances are deemed not to be meaningful parameters.
Additionally of interest is the dynamic structure of compounds 4a-c in
solution, which was studied by NMR spectroscopy. The splitting patterns of the
-46-
alkyl protons of the bridge provide some insight of the rigidity of the dimer
compared to fluxional processes on the NMR time-scale. The regions of interest of
the 'H NMR spectrum in d7-DMF are given in Table 3.
Table 3. 1 H NMR splitting of the bridging alkyl protons in compounds 4a-c.
5.0
5.5
5.5
5.0
4.5
4.5
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
2.0
2.0
1.5
ppm
1.5
pp
In 4a, a singlet is observed for all the methylene protons, implying that the
indoles may freely assume a range of dihedral angles at room temperature, resulting
in the indistinguishability of the four protons. 4b and 4c both possess splitting
-47-
patterns suggestive of distinct local environments of the alkyl protons. The four
alpha protons in 4b possess two signals near 4.9 ppm and 3.75 ppm each with
doublet of triplet substructure. The doublet multiplicity, which possesses a coupling
constant of 15 Hz in both peaks, is indicative of geminal coupling to an inequivalent
proton bound to the same carbon. The triplet splitting has coupling constantj = 4
Hz in the downfield peak and] = 9 Hz in the upfield one, resulting in different
lineshapes. A similar
150
14c .
-
.....
.
4c's alkyl alpha bridging
....
13oc.
120
OH .
soc
20 C
Ma
M
-' -a
H
H1
20 C
4.!
protons.
0
110HO
100 C
ubstructure is found in
s..
--
..
4b possesses a C2
'!-Hb
HCb
b
H
1.7
4L.5
.3
4.3
3.9
axis which passes through
t.
pp.
the beta carbon and bisects
Figure 12. H NMR spectrum detail of 4b in d 7 -DMF at T from
1
200C to 1500C
the indolyl bond. This
symmetry persists no matter what dihedral geometry the bisindole assumes, and
guarantees that the two protons labeled Ha and the two protons labeled Hb are
chemically equivalent. The diastereotopicity between these geminal positions (i.e.,
the inequivalence between Ha and Hb) implies an absence of ov-type mirror
symmetry, which can result only axial chirality, since the molecule does not possess
any chiral center (see entry 4b in Table 3). Naturally one assumes such asymmetry
would vanish if the restriction to dihedral rotation about the 2-2' indolyl bond were
relaxed. The extent of this rigidity may be quantified by variable temperature
-48-
NMR.55 A series of spectra taken of 4b (Figure 12) demonstrates that over a
temperature range to 150 'C, coupling of Ha to Hb vanishes (the doublet of triplets
structure mounds into a singlet), but the Ha peak and the Hb peak never coalesce.
Therefore 4b and 4c meet the criterion of rigidly stationing two oxygen-atoms into
proximity of one another.
The oxidation potentials of compounds of type 4a-c (data shown in Figure
13) and of type 6w(') were obtained by differential pulsed voltammetry under
conditions similar to the indole monomers. A summary of the oxidation halfwave
potential data is given by Table 4.
Table 4. Comparative oxidation halfwave potential data
E1/ 2 (mV vs.
Ag/AgC1)
Monomer
3-C Bridged
Dimer
Ionization of Carboxyl (Solvent)
-COO- (H2 0)
-COOH (DMF)
5'-R = OMe
5'-R = H
5'-R = H
5'-R = OMe
888
991
1348
1464
811
846
1276
1412
(6w')
(6w)
(3b')
(3b)
The susceptibility to oxidation of 4b-c is largely analogous to that of
monomeric 1-methyl-1H-indole-3-carboxylic acid (1472 mV and 1412 mV
compared to 1464 mV vs. Ag/AgCl), suggesting that electrons of the highestoccupied molecular orbitals in these species are not delocalized across the 2-2'
indolyl bond - a result that recapitulates the structural conclusion of rigid non-
5sDrago, RS. Physical Methodsfor Chemists (2nd ed.); Surfside SP: Gainesville, 1992.
-49-
planar geometry. In marked contrast, 4a experiences oxidation nearly 200 mV
earlier in the voltammogram. This observation corroborates the result of free
dihedral rotation in the two-carbon bridged dimer, allowing access to a planar
molecular system with extended n-orbital delocalization across both indoles.
The methoxylated derivative, 4b', the bridged dimer version of 5-methoxy-1methyl-1H-indole-3-carboxylicacid, experiences the same -100 mV shift in
response to a n-donor functional group as seen in the monomer case. The
electrochemical data of the bridged
O
OH
R4a:R=
R R
4b:
HO=H;
H;n=2.
n= 3.
O
a
bisindole carboxylic acids
4b': R =OMe; n= 3
4c: R= H; n=4.
N4
substantiates the relation of structure
to function in these organic systems,
but does not provide an avenue to
investigate 0-0 bond formation
I
1276
1472
1412
1600
1400
4 pA
catalysis. Indeed, bulk
1270
1200
electrochemical studies in which 4b'
1000
800
mV (vs. Ag/AgCI)
Figure 13. DPV of bridged bisindole carboxylic
was stoichiometrically oxidized at 1.3
V vs. Ag/AgCl results in return of the
acids. Studies conducted in DMF, on a glassy
carbon electrode.
original starting material. The most
likely explanation for this observation is a mechanism of proton-loss associated
with the oxidation, followed by H-atom abstraction from the DMF solvent. The
oxidation product is evidently reacting with solvent faster than any possible
intramolecular event because of the instability of a single O-centered radical.
-50-
If proton-transfer is indeed critical to oxidation, it is reasoned that the esterforms of 4a-c, the synthetic precursors 3a-c, which do not possess labile protons,
would show different electrochemical behavior. In fact, when 3a-c are subjected to
oxidizing environments at an electrode in DMF or acetonitrile, they all fail to exhibit
any electrochemical transformation before the solvent break-down point. Their
inability to be oxidized shows convincingly that proton transfer is critical for
accessing indole carboxyl radicals.
A solution proposed to remedy the H-atom abstraction problem was to
perform electrochemical oxidation in a solvent that is not susceptible to H-atom
absraction, namely water. Investigators prepared a water-soluble variant of 4b and
4b', namely 6w and 6w', whose preparation was illustrated in Scheme 6 prior. A
new result that emerges in water, however, is that the three-carbon bridged dimer
structure now substantially lowers the oxidation halfwave potential by nearly 150
mV. In DMF, the dimer structure had little influence, it was reasoned, because the
three-carbon bridge rigidly holds a non-planar molecular environment, decoupling
the two monomers' frontier orbitals. This result means that the dimer structure
facilitates aqueous carboxy-centered radical formation; some implications will be
considered in the discussion section.
Bulk electrolysis of 6w' was performed by preparing an anodic medium
consisting of 10.1 mg (19.6 mmol) of 6w' in 20 mL of buffered aqueous KPi at pH =
7.0. A coating of Indium Tin Oxide (ITO) on glass (8 f/sq resistivity), functioning as
-51-
a working electrode, was immersed into the aqueous solution and a constant
potential of 1.2 V vs. Ag/AgCl was maintained on this electrode.
Once two equivalents of charge had passed, the anodic solution had changed
color from nearly clear to a yellow-brown. The oxidation products were studied by
1H NMR and by electron-spray mass spectrometry. NMR confirms a single primary
product possessing the same general structure of the precursor, albeit with a loss of
symmetry given by its
possessing six distinct
. ...
-i
peaks in place of
Saryl
6w"s two. The mass
1.0401*
spectrum possesses a
4
most pronounced peak
at 471.0934 amu,
4.
matches a mono-
Iwhich
07
j- ':
2.06+0
decarboxylated
product (the calculated
.:.
100
150
200
250
300
350
400
450
500
550
600
650
Figure 14. ESI mass spectrum of the electro-oxidation products of 6w';
inset shows a detail of the main peak, corresponding to the parent
molecular ion of a singly-decarboxylated 6w'.
formula weight of 6w'
is514.38; ofthe singly
decarboyxlated
product, 470.37; and of the fully decarboyxlated product, 426.36).
-52-
Target Catalytic Cycle.
Scheme 7 illustrates a potential water oxidizing cycle that employs no metals
0
oHOo
0N
-2
, - 20'
Scheme 7. Theoretical water-splitting cycle by a bisindole carboxylate.
and highlights the catalytic "themes" that have been stressed in this chapter. In the
first step, removal of two protons and two electrons results in two carboxy radicals,
stabilized by an organic framework. Indoles are n-rich, and highly derivitizable, s6
allowing for favorable and controllable redox potential through substitution. The
model provides a physical basis for interpreting the electrochemical overpotential
in electrocatalysis. Indoles that oxidize too easily (with electron-donating groups)
will be stable enough to retain radical character and will not perform O-0
coupling. Indoles that are difficult to oxidize (such as those with electronwithdrawing groups) will have unstable radicals that should strongly favor
coupling; however, the greater potential needed to oxidize them is represented in
s6 (a) A generalreview: Humphrey, GR; Kuethe JT. Chem. Rev., 2006, 106, 7, 2875-
911. (b) Forcross-coupling: Cacchi, S; Fabrizi, G. Chem. Rev., 2005, 105, 7, 2873-920.
-53
-53--
undesired overpotential. Catalysis therefore is enabled by indoles with finely tuned
oxidation potentials, whose radicals are just unstable enough to surmount the
energy barrier to 0-0 bond formation. The oxidation potential data obtained for
monomeric indole carboxylates are highly suggestive that single electron removal
by the electrode is facilitated by prior deprotonation of the acidic carboxylic acid
group. Modification of the indole, according to the data in Table 4, is reflected by
electrochemical behavior localized on the carboxyl groups. Both of these empirical
results are encouraging vis-A-vis accomplishing the reactivity in the first step of the
proposed cycle.
The second step, which relates to the discussion on molecular geometry and
stereocatalysis, hypothesizes radical coupling forming a diacyl peroxide. In doing
so, one "harnesses" the carboxyl radicals productively toward 0-0 bond formation.
The creation of a diacyl peroxide from carboxylates indicates two of thefour
oxidations in the evolution of one equivalent of oxygen. One decomposition
pathway for a diacyl peroxide would be hydrolytic release of hydrogen peroxide; the
product of the "half-oxidation" of water. This cycle shows a bisindole carboxylate
being used as an oxidative peroxide-forming catalyst.
It is imaginable, and proposed in Scheme 7, that the diacyl peroxide system
undergoes additional oxidation. Removal of electrons would necessarily originate
from the associated n-system. Scheme 7 show a hypothetical mechanism in which
two electronically isolated aryl-centered radical states could be communicated to
the aroyl peroxide group to release the di-radical character as triplet oxygen, leaving
behind ketenes on the aryl groups. Avery unstable functional group, the ketene is
- 54-
known to react rapidly and quantitatively with water to generate a carboxylic acid.5 7
If these steps are physically realized, then they close a full catalytic oxygen-evolving
cycle, with water and oxidizing power as the only input components.
s7 See Tidwell TT et al. Tet. Lett, 1993, 34, 7, 1095 as an example.
-55-
Discussion.
Two results will be discussed, returning eventually to the initial motivation
of an organic 0-0 bond forming catalyst.
Attention must be paid to the intriguing, and in the opinion of the author,
original result obtained with regards to the anomalous 150 mV oxidation potential
shift seen in the bridged bisindole carboxylate with respect to the monomeric indole
carboxylate in neutral water. As shown by comparative oxidation potential and DFT
calculations, oxidation of anionic indole carboxylates results in oxygen-centered
spin density with little indole contribution. Therefore, the argument of extended norbital effects does not apply.
A half-wave oxidation potential for the irreversibletransformation
A-
,
A! + e'(electrode)
(3)
represents the kinetic lability for an electron in A- to become transferred to the
Fermi state of the electrode. Electron transfer is exponentially weak until the
energy at the electrode is comparable to the activation barrier, or eV/2 ~ AG*,
resulting in a peak current of charge passing from the chemical species to the
electrode. The exponential dependence of the "potential energy of the configuration
of the reacting system" on the charge transfer rate is shown explicitly in a Marcus
equation5 8 :
k = kT/2
dS Ke- U
kBST(1/
m*)
15, 155-96.
Chem.,
Phys.
1964,
Annu.
Rev.
SMarcus,
RA.
58 Marcus, RA. Annu. Rev. Phys. Chem., 1964, 15, 155-96.
-56-
(4)
where k is the rate constant, U is the "configuration energy," m* is the reduced mass
of the particle near the electrode surface, and Qis the configurational partition
function for the reactant.
As alluded earlier, AG* parameterizes the energy difference between
reactants and a particular transition state. Since these oxidation events are
chemically endothermic, by implication of the Hammond postulate, the transition
states are late, and their relative energy in reaction coordinate space is controlled
mostly by the nature of the products, or in this case, A'. It is reasoned then that a
lower halfwave potential, or lower-energy transition states, implies stabilization of
the radical species.
moo
w
°%
F1
moo
Q
0
0One
o
0.
Figure 15. Stabilization of a bisindole carboxylate-carboxyl radical.
1
possible means of
stabilization is
offered pictorially in Figure 15. The oxidized species, which has form {COO'/COOH},
is rapidly deprotenated in water admitting a carboxylate-carboxy dimer,
represented as {COO*/COO-}. This proton loss may even be coupled directly to
electron loss (in a PCET-type mechanism), although no experiment was devised to
test this hypothesis directly. A carboxylate-carboxy single radical could participate
in a cooperative radical delocalization through tunneling between the two local
carboxyl-orbital states, which might be represented by the two "resonance
contributors": {COO*/COO- and COO-/COO*}. This cooperativity renders the radical
four-atom centered rather than two-atom centered. Mechanisms like this were
-57-
initially proposed by Marcus, 57 and physical evidence of electron tunneling in singe
molecule radical-anions has been previously reported.5 9 In the present system,
they might be considered especially possible in light of the rigid proximity of these
functional groups imposed by the molecular structure.
The cooperativity mechanism in Figure 15 accounts why oxidation potentials
for bisindole dimers are anomalously small compared to the monomeric species. A
further consequence is noticed: spin density being delocalized across the carboxyl
groups insinuates electron occupation in an 0-0 orbital manifold. A chemical bond
requires spin-pairing however, and until such a radical becomes oxidized a second
time, a new bond is not physically realizable.
....
Scheme 8. Electro-oxidative decomposition pathway of 6w'
By applying this model of radical stabilization by tunneling-cooperativity, the
results of the bulk oxidation study of 6w' can be understood as well. A model for the
single-decarboxylation of 6w' at fixed potential (1.2 Vvs. Ag/AgC1) is shown in
59 Closs, GL; Miller, JR. Science, 1988, 240, 440-7.
-58-
Scheme 8. For simplicity, we employ notation that refers only to the state of the
carboxylic groups. At the ITO electrode, {CO0-/COOH} is easily oxidized by one
electron (the oxidation potential of 6w' is 811 mV), and a rapid proton loss occurs,
resulting in the stabilized intermediate, {COO*/COO-}. This stabilized radical, which
in the DMF study was catalyzing decomposition of the solvent, is not oxidizing
enough to abstract H-atoms from water. This argument is in correspondence with
known values of bond dissociation enthalpy (BDE). The BDE of HO-H is 118
kcal/mol while the BDE of HCOO-H is 112 kcal/mol, 6 0 so even a plain carboxyl
radical is not unstable enough to react with water.
Eventually {COO"/C0-} undergoes entropically-favored decarboxylation,
and in so doing, generates an even more enthalpically-unstable localized sp 2 radical.
This sp 2 radical, must be obtaining H-atoms, presumably from water since it now
has the thermodynamic drive to do so. The possibility that H-atoms are being
drawn from the molecule itself is unlikely due to the NMR spectrum showing a
single primary product. In essence, 6w' catalyzes the oxidation of water by coupling
it to the evolution of C02, using an organic carboxylate as a stoichiometric reagent.
The observed result of mono-decarboxylation is consistent with the
argument presented. A question that remains to be addressed though is why the
second carboxylic group is not evolved as CO2 as well. To support the claim of
radical stabilization cooperativity, it is possible that {-/COO-} is significantly more
60
Blanksby, SJ; Ellison, GB. Acc. Chem. Res., 2003, 36, 4, 255-63.
- 59 -
difficult to oxidize then {COO-/COOH}, indeed by perhaps as much as 150 mV.
However, this explanation is not entirely consistent with the datum of the oxidation
potential of the indole carboxylate monomer, observed to be 888 mV vs. Ag/AgCl
(see Table 4), which is much less than the fixed potential of 1.2 Vduring this
experiment. Although radical cooperativity might partially explain the high
favorability of mono-decarboxylation, we cannot presently furnish an entirely
satisfactory model for the effect.
Presently, it remains to be seen whether bridged bisindole carboxylates, or
any organic molecule for that matter, possess the capacity to catalyze 0-0 bond
formation. However, several interesting properties of these molecules were seen in
the pursuit of exploring this kind of reactivity. Bridged bisindoles take advantage of
an sp 2-sp 2 bond in tandem with an N,N'-alkyl "bridging" group to give a small
organic molecule an uncommon amount of dihedral rigidity, as seen by NMR. They
furthermore exhibit how molecular geometry and derivitization allows for tuning of
redox potential. Finally, in the case of one example, 6w', there is evidence of a
stoichiometric water oxidation process that implicates decarboxylation by bulk
electrolysis at an ITO electrode.
Radical stabilization by cooperative tunneling mechanisms has been
proposed to account for some of the interesting oxidation behavior of 6w'. If this
hypothesis is correct, then the present system is capable of coupling electrochemical
oxidation to population of a pseudo-O-0 bond. A true 0-0 bond however could
-60-
only be formed if the molecule were oxidized a second time before degradative
decarboxylation occurs. It is also possible that the specific system studied simply
does not possess the ability to form a stable intramolecular diacyl peroxide.
Future efforts of design of organic catalysts will need to take into account
means to protect against kinetically compelling competitor mechanisms such as
decarboxylation. Nonetheless, the three themes explored here, id est, oxygencentered reactivity, dimeric structure, and geometric rigidity, are shown to be highly
general factors to be considered in the catalysis of 0-0 bond formation.
-61-
IV. Supplementary Information (SI)
IV-1. Synthesis of Hangman Catalysts..........................................................................63
IV-2. Time Course Plots of Hangman Catalysts.............................................................66
IV-3. Characterization Data of Bisindoles.................................................................. 68
IV-4. Synthesis of Bisindoles.......................................................................................
73
IV-5. NM R spectra of Bisindoles.................................................................................... 82
-62-
IV-1. Synthesis of Hangman Catalysts (Section II).
2 4-(5,5'-Dimethyl-1,3-dioxane)-5-bromo-2,7-di-tert-butyl-9,9-dimethylxanthene.
To a
solution of 1.00 g of xanthene dibromide, 1, (2.08 mmol, 1 equiv) dissolved in 40 mL dry THF in an
oven-dried round-bottom flask, immersed in a C0 2/acetone bath at -78 oC, under an inert
atmosphere of N2 is added 1.2 mL of Phenyllithium (1.8 M, 2.16 mmol, 1.04 equiv) by syringe over a
period of 10 min. After stirring at -78 oC under an N2 atmosphere for 1 h, dry DMF (1 mL) was added
and the mixture was warmed to room temperature, and stirred for an additional hour. The
unreacted organolithium was quenched by addition of water (30 mL); the organic layer was gathered
and the organic solvent was removed by rotary evaporation. The white powder was redissolved in
50 mL of toluene along with 230 mg of neopentyl glycol (2.17 mmol, 1.04 equiv), and 5 mg of
benzenesulfonic acid. The solution, in a 100mL round-bottom flask fitted with a Dean-Stark trap and
condensing tube, was placed under an inert N2 atmosphere, and refluxed for 2h. Afterward, the
reaction mixture was washed with 50 mL saturated aqueous NaHC0 3 and then 50 mL H20. After
gathering the organic layer, and drying it with treatment of Na2SO 4, it was stripped by rotary
evacuation. The resulting solid was purified by column chromatography in silica, with CH2C12 as
eluent. The product, 2, was procured as a white solid in overall 75% yield.
3 4-Formyl-5-hydroxycarbonyl-2,7-di-tert-butyl-9,9-dimethylxanthene.
To a solution of 1.03 g
of bromide, 2, (2.00 mmol, 1 equiv) dissolved in 40 mL dry THF in an oven-dried round-bottom flask,
immersed in a C02/acetone bath at -78 oC, under an inert atmosphere of N2 is added 1.2 mL of
Phenyllithium (1.8 M, 2.16 mmol, 1.08 equiv) by syringe over a period of 10 min. After stirring at -78
oC under an N2 atmosphere for 1 h, C0 2 gas was bubbled into the organolithium at a rapid rate until
the yellow color of the solution faded. The mixture was allowed to warm to room temperature and
continued stirring overnight. The unreacted organolithium was quenched by addition of 2 M HCI (15
mL); the organic layer was gathered and the organic solvent was removed by rotary evaporation. A
resulting white material was filtered and washed with water. The acetal was dissolved in a solution
-63-
consisting of 10 mL of trifluoroacetic acid 3 mL of water. This solution was allowed to stir at room
temperature for 24 h and then concentrated under vacuum to deliver an orange oil. 20 mL of water
was added, and the resulting precipitate was filtered. Purification by column chromatography in
silica, using CH2C12 as eluent, afforded 3 as a white powder in 77% yield.
4 4-Formyl-5-methoxycarbonyl-2,7-di-tert-butyl-9,9-dimethylxanthene.
A solution of 1.00 g of
3 (2.53 mmol, 1 equiv) was prepared in 50 mL of methanol. 2 mL of H2S0 4 was added and the
solution stirred under reflux for 4 h. Afterwards, the solvent was removed in vacuo, and 20 mL of
water was added to the film formed on the walls of the round-bottom flask. The resulting precipitate
was filtered, and the solid was redissolved in 50 mL of CH2C12 . This solution was washed with 15%
(vol/vol) HCI in water; the organic layer was gathered, dried over Na 2SO4, and stripped of solvent by
rotary evaporation. This solid was purified by column chromatography in silica, with CH2C12 eluent,
furnishing 0.96 g of ester, 5, as a white powder in 93% yield.
Sa-c. A solution of aldehyde 4 (0.41 g, 1 mmol, 1 equiv), an aryl aldehyde (mesityl aldehyde to form
Sa, pentafluorophenyl aldehyde to form 5b, or 2,5-dimethoxyphenyl aldehyde to form 5c, 15 mmol,
15 equiv), and pyrrole (1.11 mL, 16 mmol, 16 equiv) dissolved in CHC13 in a round-bottom flask was
purged with N2 for 20 minutes and stirred. Then, a solution prepared of BF3 -OEt 2 in CHC1 3 (0.67 mL,
5.28 mmol, 5.28 equiv), was added via syringe into the round-bottom flask. This solution was stirred
for 90 min in the dark under an inert N2 atmosphere. At this point, 2.72 g of 2,3-dichloro-5,6dicyano-1,4-benzoquinone (12 mmol, 12 equiv) was added to the reaction, and the solution was
allowed to stir for an additional hour under N2. The solvent was removed by rotary evaporation. The
resulting dark residue on the flask was redissolved in 300 mL of CH2 C12 and filtered. The filtrate was
loaded onto a silica column packed with CH2C1 2 and eluted continuously until no more porphyrin
product was to be found in the run-off, as determined by thin-layer chromatography. The run-off
was condensed in vacuo and recrystallized several times from CH2C12 and MeOH. Final purification
was conducted by a second silica column with gradient elution: originally, the eluent had
composition of 4:1 hexanes/CH2Cl 2 and the final composition was 2:1 hexanes/CH 2C2. The entire
-64-
process afforded free-base porphyrins in 20-30% yield from the spacer, 4. This porphyrin ester was
hydrolyzed by dissolving it in a mixture of 20 mL acetic acid and 5 mL H 2 SO4 . The mixture was
diluted with 6 mL H2 0 and refluxed under N2 in the dark for 7 days. The reaction was cooled to room
temperature, and 50 mL of CH 2 C12 was added. The organic layer was extracted, dried over Na 2 SO 4 ,
and the solvent was stripped away by rotary evaporation. Purification by column chromatography
on silica with CH2C12 as eluent yielded a free-base porphyrin with a carboxylic acid hanging
functional group in near quantitative yield from the ester. These compounds were dark violet
colored solids.
6a-c. To a solution of 5 (0.51 mmol, 1 equiv) in 30 mL CH3 CN is added 350 mg FeBr 2 (1.62 mmol,
3.17 equiv). The solution is placed in a round-bottom flask equipped with a condenser, refluxed
under an inert N2 atmosphere for 8 h, opened to air, and then brought to dryness under vacuum. The
solids are redissolved in 100 mL of CH2C12 and purified by column chromatography on silica, eluting
first with CH2C12 to remove less polar impurities, and then with 5% MeOH in CH2C12 to elute out the
product. The fractions with porphyrin, as determined by thin-layer chromatography, are
concentrated under reduced pressure; then the solution is treated with HC1, as described in the
preparation of 5, to furnish the protonated carboxylic acid, 6, in 80-90% yield.
-65-
IV-2. Time Course Plots of Hangman Catalysts (Section II)
Fluoronated Hangman (6b)
4.5
-4
E3.5
3
g.5
S2
,I1.5
Lb.5
0 0
0
10
20
40
30
Time Elapsed [min]
50
60
70
50
60
70
Methoxylated Hangman (6c)
4
-P.5
E 3
02.5
> 2
>1 .5
o.5
0 0...
0
10
20
40
30
Time Elapsed [min]
-66-
Time Course Plots of controls.
FeCI(TMP) Control
4
3.5
r
3
v
2.5
2
Lu 1.5
x 0.5
0
o
0
-0.50
Time Elapsed [min]
FeCI(TMP) + 1 equiv PhCOOH Control
6
05
u2
oQo
00
0
10
20
40
30
Time Elapsed [min]
-67-
50
60
70
IV-3. Characterization Data of Bisindoles (Section III)
2a Dimethyl 1,1'-(ethane-1,2-diyl)bis(1H-indole-3-carboxylate).
95% yield. 1H NMR (500 MHz,
CDC13, 6): 8.19-8.17 (m, 2H), 7.37 (s, 2H), 7.30-7.23 (m, 4H), 7.17-7.15 (m, 2H), 4.53 (s, 4H), 3.85 (s,
6H). 13C NMR (125 MHz, CDC13, 6): 165.17, 136.09, 134.00, 126.93, 123.44, 122.43, 122.27, 109.13,
108.38, 51.17, 46.63. HRESI-MS ([M+Na]) C22 H20NaN20 4 m/z Calcd 399.1315, found 399.1329.
3a 60% yield. 1H NMR (500 MHz, CDC13, 6): 8.23-8.21 (m, 2H), 7.37-7.28 (m, 6H), 4.47 (s, 4H), 3.86
(s, 6H). 13C NMR (125 MHz, CDC13, 6): 166.15, 135.98, 130.67, 128.17, 124.84, 123.13, 122.92, 109.64,
108.33, 51.92, 41.63 HRESI-MS ([M+Na]) C22H18NaN20 4 m/z Calcd 397.1159, found 397.1177.
4a 93% yield. 'H NMR (300 MHz, DMF-d 6, 6): 12.75 (s, 2H), 8.346 (d,] = 8 Hz, 2H), 7.872 (d,] = 8 Hz,
2H), 7.52 (td,1] = 7 Hz,] 2 = 1 Hz, 2H), 7.42 (td,1] = 7 Hz,] 2 = 1 Hz, 2H), 4.90 (s, 4H). 13C NMR (125
MHz, DMF-d 6, 8): 166.92, 136.27, 130.98, 128.22, 124.13, 122.32, 122.15, 110.85, 109.03, 41.74.
HRESI-MS ([M-H]) C20H13N20
4
m/z Calcd 345.0881, found 345.0874.
2b Dimethyl 1,1'-(propane-1,3-diyl)bis(1H-indole-3-carboxylate). 95% yield. 1H NMR (500 MHz,
CDC13, 6): 8.21-8.19 (m, 2H), 7.76 (s, 2H), 7.31-7.24 (m, 4H), 7.20-7.18 (m, 2H), 4.155 (t, = 7 Hz, 4H),
3.91 (s, 6H), 2.50 (q,j = 7 Hz, 2H). 13C NMR (125 MHz, CDC13, 6):165.40, 136.38, 133.81, 126.91,
123.29, 122.34, 122.16, 109.82, 107.95, 51.21, 43.93, 29.81. HRESI-MS ([M+Na]) C23H22NaN20 4 m/z
Calcd 413.1472, found 413.1472.
3b 47% yield. 1H NMR (300 MHz, CDC13, 6): 8.35-8.32 (m, 2H), 7.41-7.26 (m, 6H), 4.60-4.52 (m, 2H),
3.88-3.76 (m, 2H), 3.77 (s, 6H), 2.47-2.38 (m, 2H). 13C NMR (125 MHz, CDC13, 6): 165.14, 135.83,
134.01, 127.19, 123.85, 122.68, 122.25, 109.04, 108.62, 51.13, 40.52, 29.71. HRESI-MS ([M+Na])
C23H2oNaN20
4
m/z Calcd 411.1315, found 411.1315.
4b 96% yield. 1H NMR (500 MHz, DMF-d 6 , 6): 12.45 (brs, 2H), 8.46 (d,] = 9 Hz, 2H), 7.96 (d,] = 8 Hz,
2H), 7.53 (m, 2H), 7.46 (m, 2H), 5.03 (dt,Ji = 15 Hz, J2 = 4 Hz, 2H), 3.94 (dt,Ji = 15 Hz,]2 = 9 Hz, 2H),
2.64 (m[ttd], 2H). 13C NMR (125 MHz, DMF-d 6 , 6): 166.47, 136.86, 135.39, 128.17, 124.08, 122.82,
-68-
122.35, 110.89, 109.80, 41.27, 35.82. HRESI-MS ([M-H]) C21Hs5N2 0 4 m/z Calcd 359.1037, found
359.1020.
2c Dimethyl 1,1'-(butane-1,3-diyl)bis(IH-indole-2-iodo-3-carboxylate).
85% yield. 1H NMR (500
MHz, CDC13, 6): 8.13 (m, 2H), 7.29 (m, 2H), 7.22 (m, 4H), 4.31 (m, 4H), 3.98 (s, 6H), 1.91 (m, 4H).
13C
NMR (125 MHz, CDC13, 6): 165.51, 138.58, 128.17, 123.88, 122.50, 112.36, 110.62, 94.74, 51.86,
48.06, 41.70, 27.52. HRESI-MS ([M-H]) C23H20N2 0 4 12 m/z Calcd 642.2248, found 642.9564.
3c 32% yield. 1H NMR (500 MHz, CDC13, 5): 8.34 (m, 2H), 7.46-7.35 (m, 6H), 4.46 (dd,]J = 15 Hz,]2 = 6
Hz, 2H), 3.74 (s, 6H), 3.50 (dd,J] = 15 Hz,] 2 = 11 Hz, 2H), 2.12 (m, 2H), 1.92 (m, 2H). 13C NMR (125
MHz, CDC13 , 6): 165.73, 136.31, 134.87, 127.86, 124.17, 123.34, 123.08, 110.38, 108.90, 51.69, 44.03,
28.02. HRESI-MS ([M+Na]) C24 H22 NaN 20 4 m/z Calcd 425.1472, found 425.1479.
4c 95% yield. 1H NMR (500 MHz, DMF-d 6, 6): 12.19 (s, 2H), 8.31 (d,] = 8 Hz, 2H), 7.73 (d,] = 8 Hz,
2H), 7.38 (td,J] = 8 Hz,] 2 = 1 Hz, 2H), 7.33 (td,j] = 8 Hz,]2 = 1 Hz, 2H), 4.67 (dd,Jl = 12 Hz,]2 = 6 Hz,
3
2H), 3.44 (dd,]1 = 12 Hz,]2 = 15 Hz, 2H), 2.12 (ddJ] = 12 Hz,]2 = 6 Hz, 2H), 1.79 (m, 2H). 1 C NMR (125
MHz, DMF-d 6 8): 166.38, 136.64, 135.71, 128.52, 123.93, 122.90, 122.69, 111.44, 109.32, 44.10 28.46.
HRESI-MS ([M+Na]) C22H18NaN 2 0 4 m/z Calcd 397.1159, found 397.1150.
2b' Dimethyl 1,1'-(propane-1,3-diyl)bis(S-methoxy-1H-indole-3-carboxylate). 99% yield. 1H
NMR (300 MHz, CDC13 , 6): 7.68 (s, 2H), 7.67 (d,] = 2.4 Hz, 2H), 7.07 (d,] = 9Hz, 2H), 6.89 (dd,] = 9 Hz,
3
J = 2.4 Hz, 2H), 4.10 (t,] = 6.9 Hz, 4H), 3.904 (s, 6H), 3.90 (s, 6H), 2.47 (q,] = 6.9 Hz, 2H). 1 C NMR (125
MHz, CDC13, 6): 166.05, 156.71, 134.36, 131.89, 128.39, 114.34, 111.26, 107.80, 103.82, 56.59, 51.74,
45.90, 44.62, 30.36. HRESI-MS ([M+Na]) C2 sH2 6NaN 206 m/z Calcd 473.1683, found 473.1672.
3b' 84% yield. 'H NMR (500 MHz, CDC13, 6): 7.81 (d,J = 2.5 Hz, 2H), 7.29 (d,] = 9Hz, 2H), 7.00 (dd,]=
9 Hz,] = 2.5 Hz, 2H), 4.50-4.45 (m, 2H), 3.94 (s, 6H), 3.84-3.77 (m, 2H), 3.74 (s, 6H), 2.43-2.38 (m,
2H). 13C NMR (125 MHz, CDC13, 6): 165.40, 156.08, 134.09, 130.94, 128.03, 114.84, 109.94, 107.83,
103.19, 55.93, n51.06, 40.78, 30.00. HRESI-MS ([M+H]) C25 H2 5N 20 6 m/z Calcd 449.1707, found
449.1717.
-69-
4b' 86% yield. 1H NMR (500 MHz, DMSO-d 6, 6): 11.88 (s, 2H), 7.65 (d,] = 9 Hz, 2H), 7.61 (d,] = 3 Hz,
2H), 6.95 (dd,1] = 9 Hz,Jz = 3 Hz, 2H), 4.72-4.68 (m, 2H), 3.82 (s, 6H), 3.62-3.55 (m, 2H), 2.34-2.31 (m,
2H). 13C NMR (125 MHz, DMSO-d 6 , 6): 165.49, 155.15, 134.23, 130.64, 127.28, 113.46, 111.10, 107.76,
102.63, 55.37, 40.31, 29.52. HRESI-MS ([M+H]) C23H21N20
6
m/z Calcd 421.1394, found 421.1391.
2w Dimethyl 1,1'-(2-(tert-butyldimethylsilyloxy)propane-1,3-diyl)bis(1H-indole-3carboxylate) 58% yield. 1H NMR (500 MHz, CDC13, 6): 8.20-8.18 (m, 2H), 7.79 (s, 2H), 7.29-7.23 (m,
2H), 7.13-7.12 (m, 2H), 4.34 (q,] = 5.5 Hz, 1H), 4.13-4.12 (d,] = 5.5 Hz, 4H), 3.91 (s, 6H), 0.83 (s, 9H), 0.47 (s, 6H).
13C
NMR (125 MHz, CDC13, 6): 165.36, 136.64, 135.09, 126.81, 123.32, 122.30, 122.13,
109.69, 107.97, 69.94, 51.20, 50.91, 25.83, 17.84, 5.48. HRESI-MS ([M+H]) C29 H37 N205Si m/z Calcd
521.2466, found 521.2453.
3w 64% yield. 1H NMR (500 MHz, CDC13, 6): 8.33 (d,] = 8 Hz, 2H), 7.42-7.32 (m, 6H), 4.60 (m, 1H),
4.50 (dd,J] = 14 Hz,]z = 6.5, 1H), 4.40 (I = 15 Hz, 1H), 3.88 (m, 1H), 3.78 (s, 6H), 3.60 (dd,]l = 14 Hz,]2
= 10 Hz, 1H), 0.91 (s, 9H), 0.21 (d,] = 30 Hz, 6H). 13C NMR (125 MHz, CDC13,
S): 165.77, 165.66,
138.00, 136.67, 134.17, 134.12, 127.76, 127.52, 124.61, 124.53, 123.44, 123.03, 122.91, 110.48,
109.78, 109.36, 72.25, 51.80, 51.75, 50.55, 47.46, 26.36, 18.69, -3.91, -3.99. HRESI-MS ([M+H])
C29 H3sN20sSi m/z Calcd 519.2310, found 519.2311.
4w 84% yield. 1H NMR (500 MHz, DMSO-d 6, 5): 8.13 (m, 2H), 7.82 (d,]2 = 9 Hz, 1H), 7.67 (d,]2 = 9 Hz,
1H), 7.37 (t,] = 7.2 Hz, 2H), 7.29 (t,] = 7.2 Hz, 2H), 5.77 (d,] = 4 Hz, 1H), 4.90 (m, 1H), 4.60 (s, 1H),
4.57 (s, 1H), 3.79 (d,] = 12.8 Hz, 1H), 3.65 (d,] = 4 Hz, 6H), 3.16 (d,] = 5.2 Hz, 1H). 13C NMR (125
MHz, DMSO-d 6, 6): 165.39, 165.31, 138.25, 137.19, 134.55, 134.45, 127.22, 127.14, 124.83, 124.70,
123.20, 123.07, 122.52, 122.32, 112.01, 111.70, 108.87, 108.31, 70.92, 51.88, 51.87, 50.43, 47.19.
HRESI-MS ([M+H]) C23H21N20s m/z Calcd 405.1554, found 405.1447.
Sw 75% yield. 1H NMR (500 MHz, DMSO-d 6, 6): 8.15 (dd,J] = 8 Hz,]z = 3 Hz, 2H), 7.76 (dd,l] = 12 Hz,
]2 = 8 Hz, 2H), 7.39 (q,] = 7 Hz, 2H), 7.31 (t,] = 7 Hz, 2H), 5.11 (m, 1H), 5.03-4.99 (m, 1H), 4.95 (d,] =
15.8 Hz, 1H), 4.02 (dd,J] = 16 Hz,]z = 3 Hz, 1H), 3.66 (d,] = 4 Hz, 6H), 3.51 (dd,1] = 15 Hz,]z = 10 Hz,
1H). 13C NMR (125 MHz, CDC13, 6): 165.30, 165.25, 138.06, 137.27, 134.35, 134.17, 127.27, 127.15,
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125.05, 125.02, 123.36, 123.26, 122.62, 122.39, 111.97, 111.54, 109.38, 109.80, 74.78, 51.94, 51.93,
48.12, 48.02.31p NMR (202 MHz, DMSO-d 6, 8): -0.13, -1.10. HRESI-MS ([M-H]) C23H2oN20 8P m/z Calcd
483.0963, found 483.0987.
6w 100% yield. 1H NMR (500 MHz, DMSO-d 6, 6): 8.12 (d,] = 12.7 Hz, 2H), 7.73 (t,] = 13 Hz, 2H), 7.25
(m, 4H), 4.99 (s, 2H), 4.95 (m, 1H), 3.88 (s, 1H), 3.83 (s, 1H), 3.40 (m, 2H). 31P NMR (202 MHz, DMSOd 6 , 6): -0.40. HRESI-MS ([M-H]) C21H16N20 8 P m/z Calcd 455.0650, found 455.0663.
2w' Dimethyl 1,1'-(2-(tert-butyldimethylsilyloxy)propane-1,3-diyl)bis(5-methoxy-1H-indole3-carboxylate). 43% yield. 1H NMR (500 MHz, CDC~1, 6): 7.72 (s, 2H), 7.66 (d,] = 2.5 Hz, 2H), 7.00 (d,
i = 9 Hz, 2H), 6.88 (dd,] = 9 Hz,] = 2.5 Hz, 2H), 4.39 (q,] = 6 Hz, 1H), 4.07 (d,] = 6 Hz, 4H), 3.90 (s, 6H),
3.89 (s, 6H), 0.83 (s, 9H), 0.45 (s, 6H). 13C NMR (125 MHz, CDC13, 5): HRESI-MS ([M+H]) C31H 41N20 7 Si
m/z Calcd 581.2678, found 581.2660.
3w' 47% yield. 1H NMR (500 MHz, CDC13, 6): 7.79 (t,] = 2.5 Hz, 2H), 7.29 (d,] = 9 Hz, 1H), 7.27 (d,] = 9
Hz, 1H), 7.02 (dd,] = 9 Hz,] = 2.5 Hz, 1H), 6.99 (dd,] = 9 Hz,] = 2.5 Hz, 1H), 4.60-4.56 (m, 1H), 4.42
(dd,] = 14 Hz,] = 7 Hz, 1H), 4.31 (d,] = 15 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.86 (dd,] = 15 Hz,] = 9
Hz, 1H), 3.75 (s, 6H), 3.57 (dd,] = 15 Hz,] = 10 Hz, 1H), 0.89 (s, 9 H), 0.22 (s, 3H), 0.16 (s, 3H). 13C
NMR (125 MHz, CDC13, 8): 165.45, 165.35, 156.19, 156.13, 133.67 (2C), 132.57, 131.21, 128.03,
127.74, 115.01 (2C), 110.81, 109.69, 108.38, 107.97, 103.31, 102.75, 71.92, 55.95, 55.90, 51.11 (2C),
50.22, 47.17, 25.78, 18.08, -4..50, -4.58. HRESI-MS ([M+H]) C31H3 9NZO 7 Si m/z Calcd 579.2521, found
579.2506.
4w' 84% yield. 1H NMR (500 MHz, CDC13, 8): 7.76 (d,] = 2.5 Hz, 1H), 7.69 (d,] = 2.5 Hz, 1H), 7.33 (d,]
= 9 Hz, 1H), 7.15 (d,] = 9 Hz, 1H), 7.01 (t,] = 2.5 Hz, 1H), 6.99 (t,] = 2.5 Hz, 1H), 4.58-4.54 (m, 1H),
4.41-4.34 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.80 (dd,] = 15 Hz,] = 3.5 Hz, 1H), 3.71 (s, 3H), 3.67 (s,
3H), 3.47 (dd,] = 15 Hz,] = 10 Hz, 1H), 2.56 (brs, 1H). 13C NMR (125 MHz, CDC13, 6): 165.49, 165.26,
156.22, 156.17, 133.81, 133.42, 132.56, 131.16, 127.84, 127.56, 115.06, 115.03, 110.43, 110.16,
108.44, 108.20, 103.45, 103.28, 71.62, 56.03, 55.94, 51.17, 51.10, 49.63, 46.37. HRESI-MS ([M+Na])
C2sH24 NaN20 7 m/z Calcd 487.1476, found 487.1460.
- 71 -
5w' 98% yield. 1 H NMR (500 MHz, CD3 OD, 6): 7.68 (d,] = 2.5 Hz, 2H), 7.55 (d,j = 9.5 Hz, 2H), 7.02 (dd,
] =9 Hz,] = 2.5 Hz, 2H), 7.00 (dd,] = 9 Hz,] = 2.5 Hz, 2H), 5.16-5.12 (m, 1H), 4.94-4.90 (m, 1H), 4.84
(d,]= 16 Hz, 1H), 3.93 (dd,J= 16 Hz,]= 2.5 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H), 3.73 (s,
3H), 3.61 (dd,J = 14.5 Hz,] = 9.5 Hz, 1H). 13C NMR (125 MHz, CD3 0D, 6): 167.08, 166.95, 157.68,
157.63, 135.11, 134.97, 133.80, 132.87, 128.85, 128.64, 115.84, 112.30, 111.55, 109.32, 108.79,
103.99, 103.62, 76.20, 56.13, 56.09, 51.50, 46.18. 31p NMR (202 MHz, DMSO-d 6, 6): -0.84. HRESI-MS
([M-H]) C25H24N2 0 10P m/z Calcd 543.1174, found 543.1182.
6w' 84% yield. 1H NMR (500 MHz, DMSO, 6): 11.8 (brs, 4H), 7.64-7.58 (m, 4H), 7.00-6.97 (m, 2H),
5.06-5.01 (m, 1H), 4.92 (dd,] = 14.5 Hz,] = 7H, 1H), 4.85 (d,] = 16 Hz, 1H), 3.93-3.89 (m, 1H), 3.83 (s,
3H), 3.82 (s, 3H), 3.42 (dd,] = 14.5 Hz,] = 10 Hz).
13
C NMR (125 MHz, DMSO, 6): 165.42, 165.37,
155.31, 155.27, 133.66, 133.49, 131.92, 131.09, 127.24, 127.07, 113.88, 113.80, 111.43, 111.04,
108.87, 108.27, 102.75, 102.45, 73.96, 55.42, 55.40, 46.89, 44.86.31P NMR (202 MHz, DMSO-d 6 , 8): 1.16. ( HRESI-MS ([M-H]) C23H20N2 010 P m/z Calcd 515.0861, found 515.0862.
1
7 Methyl 5-methoxy-1H-indole-3-carboxylate. 89% yield. H NMR (500 MHz, CDC13, 6): 8.89 (brs,
1H), 7.86 (d,] = 3Hz, 1H), 7.67 (d,] = 2.5 Hz, 1H), 7.29 (d,]= 9 Hz, 1H), 6.91 (dd,] = 9 Hz,] = 3 Hz, 1H),
3.92 (s, 3H), 3.87 (s, 3H). 13C NMR (125 MHz, CDC13, 6): 166.04, 155.92, 131.46, 131.11, 126.78,
113.80, 112.53, 108.28, 102.78, 55.86, 51.22. HRESI-MS ([M+H]) C11H12N0 3 m/z Calcd 206.0812,
found 206.0815.
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IV-4. Synthesis of Bisindoles (Section III)
Unless otherwise noted, all starting materials used in synthesis were >95% pure, Sigma-Aldrich
chemicals, and all solvents used were Sigma-Aldrich CHROMASOLV-quality, >99.9% pure.
2a Dimethyl 1,1'-(ethane-1,2-diyl)bis(1H-indole-3-carboxylate).
To an oven-dried round-
bottom flask was added 0.966 g (5.51 mmol, 1 equiv) of methyl 1H-indole-3-carboxylate and a stir
bar. The RB flask was subsequently introduced into a glove box, in which 20 mL of dry DMF was
added until the material was dissolved, and 0.134 g (5.57 mmol, 1.01 equiv) of dry NaH was directly
added. After allowing all H2 to expel from the RB Flask, it was septum sealed, exported from the
glove box, and placed in an oil-bath kept at the steady temperature of 75-80 oC. The septum was
quickly removed, and added into the mixing solution was 1.024 g ethylene di(p-toluenesulfonate)
(2.78 mmol, 0.500 equiv); after which, the septum was replaced forthwith. The brown solution was
allowed to stir for 4 h, after which the reaction mixture was concentrated via rotary evacuation with
gentle heat applied to yield a brown residue. The residue was re-dissolved in 250 mL CH2C1 2, and
washed once by 250 mL of saturated NaHCO3 and once by 250 mL brine. The organic phase was
collected, dried over Na 2SO4, and stripped by rotary evacuation, yielding a brown near-pure product
in overall 95% yield.
3a. The procedure used for the oxidative coupling of Dimethyl 1,1'-(ethane-1,2-diyl)bis(1H-indole-3carboxylate) was analogous to that used for the coupling of the propane derivative; see procedure for
3b. On a scale of.915 g of 2a, 0.550 g of an off-white powder was isolated upon chromatography in
overall 60% yield.
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4a. The procedure used for the hydrolysis of 3a was analogous to that used for the hydrolysis of the
propane derivative; see procedure for 4b. On a scale of 0.223 g of 3a, .192 g of a bright yellow
precipitate was gathered from the frit after filtration, in overall 93% yield.
2b Dimethyl 1,1'-(propane-1,3-diyl)bis(1H-indole-3-carboxylate).
To an oven-dried round-
bottom flask was added 2.80 g (15.98 mmol, 1 equiv) of methyl 1H-indole-3-carboxylate and a stir
bar. The RB flask was subsequently introduced into a glove box, in which 30 mL of dry DMF was
added until the material was dissolved, and 0.387 g (16.13 mmol, 1.01 equiv) of dry NaH was directly
added. After allowing all H2 to expel from the RB Flask, it was septum sealed, exported from the
glove box, and placed in an oil-bath kept at the steady temperature of 75-80 OC. By syringe, 816 mL
1,3-dibromopropane (7.99 mmol, 0.500 equiv) was quickly injected into the reaction medium. The
brown solution was allowed to stir for 4 h, after which the reaction mixture was concentrated via
rotary evacuation with gentle heat applied to yield a brown residue. The residue was re-dissolved in
400 mL CH2 C12 , and washed once by 300 mL of saturated NaHCO 3 and once by 250 mL brine. The
organic phase was collected, dried over Na 2SO4, and stripped by rotary evacuation, yielding a brown
near-pure product in overall 95% yield.
3b. An oven-dried Schlenk flask, charged with 2.51 g (6.42 mmol, 1 equiv) 3a and a stir-bar, and a
second round-bottom flask charged with a stir-bar were introduced into the glove box. 3a was
dissolved with 80 mL dry THF (filtered on celite and dried over molecular sieves). To the RB flask
was added 2.16 g copper(II) chloride (16.05 mmol, 2.5 equiv) and 50 mL of dry THF, forming a
suspension. The two flasks were both septum sealed and exported from the glove box. The Schlenk
flask was loaded into an acetone/dry ice bath stabilized at temperature -80 OC and connected to a
positive pressure of N2 from a Schlenk line. The RB flask was placed in a water/ice bath at
temperature 0 oC, adjacent to the Schlenk flask. Then, drop-wise 7.30 mL of 2.2 M nBuLi (16.05
mmol, 2.5 equiv) was added to the Schlenk flask; the mixture was allowed to stir for 20 min, at which
- 74-
point the reaction medium of the Schlenk flask was transferred slowly to the stirring CuC12
suspension via cannula. The CuC12 went into solution and rapidly became dark-green colored, and
was allowed to stir for 10 min. Afterward, the green solution was concentrated in vacuo and rediluted with 150 mL EtOAC. This solution was washed twice by 150 mL 1 M HC1, and once by 100 mL
brine - the dark color of the organic layer vanished in the acid wash. The organic phase was
collected, dried over Na2 SO4, and stripped by rotary evacuation. The crude structure was assessed
positively by NMR, and then purified by chromatography on alumina with 4:1 CH2 Cl2:Hx-H as eluent.
The product eluted later from the column and was identified as a large dot with Rf ~ 0.25 on alumina
TLC that appears blue when visualized with 210 nm light from a Hg-lamp. After chromatography,
0.118 g of product was yielded as an off-white powder in overall 47% yield.
4b. 949 mg of 3b (1.45 mmol) was added to a round-bottom flask, charged with a stir bar. Added to
the flask was 20 mL of a 5:1 DMSO:3M KOH(aq) solution. The suspension was initially set to stir at
80 oC in an oil bath. Over the course of 2 h, the material dissolved into the aqueous solution as it was
hydrolyzed. The reaction's progress was assessed as complete once all material had dissolved. The
solution was diluted with 15 mL H2 0 and the organic carboxylic acid was precipitated by dropwise
addition of 5 mL glacial AcOH. The precipitate was gathered via vacuum filtration over a fine frit and
was allowed to air dry over the frit overnight. The dry off-white powder-like material was collected
from the frit in 96% yield.
[2c] v Dimethyl 1,1'-(butane-1,4-diyl)bis(1H-indole-2-iodo-3-carboxylate). To an oven-dried
round-bottom flask was added a stir-bar and 4.40 g (14.61 mmol, 1 equiv) of methyl 2-iodo-1Hindole-3-carboxylate, 4.0 g of K2 C0 3 (28.94 mmol, 2.0 equiv). The RB flask was introduced into the
V The preparation reported here is for Dimethyl 1,1'-(butane-1,4-diyl)bis(1H-indole-2-iodo-3carboxylate) rather than Dimethyl 1,1'-(butane-1,4-diyl)bis(1H-indole-3-carboxylate), and so
corresponds to an iodinated form of the 2c as it appears in Scheme 5.
-75-
glove box where 20 mL of dry DMF was added. The flask was septum-sealed, and transferred to the
fume hood, where it was placed in an oil bath at -60 oC. 960 mL of 1,4-diiodobutane (7.30 mmol,
0.500 equiv) was added via syringe and allowed to react for 2 h. The mixture was concentrated in
vacuo, then diluted with 400 mL of CH2C12 . This resulting solution was washed twice with 200 mL
H2 0. 200 mL of CH2C12 was added to the combined aqueous phases to extract any remaining
organics. All organic layers were combined and washed once more with 200 mL brine. The organic
phase was collected and dried over Na 2SO4, and stripped by rotary evacuation. The material was
purified under recrystallization with the following procedure: the tan-colored powder was dissolved
into a minimal amount (25 mL) of hot CH2C12, which was allowed to cool for 5 min. Then, 70 mL of
MeOH was added, and the mixture was allowed to let sit at room temperature for -2 h. Near-white
crystals were found at the bottom of the flask; the mother liquor was decanted and 4.03 g of the
crystalline material was gathered in overall 85% yield.
3c. 1.75 g (2.70 mmol, 1 equiv) of 2c, 1.0 g of copper turnings (16.2 mmol, 6 equiv), and a stir bar
were charged into an oven-dried round bottom flask, equipped with a condensing tube. 45 mL of
anhydrous DMF was added via syringe, and the reaction apparatus was placed in a sand bath in a
heating mantle set initially at 50 oC. The heat applied was increased until a steady reflux in DMF was
observed, at which point the reaction was allowed to stir at reflux overnight. Afterward, the reaction
medium was concentrated in vacuo, and filtered to remove the excess insoluble copper, rinsing first
with hot DMF and then with hot CH2 C12 . The filtrate was diluted with 20 mL CH2C1 2 , washed once
with 200 mL 1 M HC1, once with 200 mL H20, and once with 200 mL brine. The organic phase was
dried over Na2 SO4 , and stripped via rotary evaporation. The solid material was purified by
chromatography in silica with CH2C02 as eluent to yield 350 mg of a colorless solid, furnishing the
pure product in 32% yield.
-76-
4c. The procedure used for the hydrolysis of 3c was analogous to that used for the hydrolysis of the
propane derivative; see procedure for 3b. On a scale of 0.299 g of 3c, 0.192 g of a bright yellow
precipitate was gathered from the frit after filtration, in overall 95% yield.
2b' Dimethyl 1,1'-(propane-1,3-diyl)bis(5-methoxy-lH-indole-3-carboxylate).
The di-
alkylation procedure of methyl 5-methoxy-1H-indole-3-carboxylate to synthesize 2b' was analogous
to that used for the non-methoxy derivative; see procedure for 2b. On a scale of 2.039 g of methyl 5methoxy-1H-indole-3-carboxylate, 2.275 g of a near-pure tan-colored powder was collected after
rotary evaporation in quantitative yield.
3b'. An oven-dried Schlenk flask, charged with 1.13 g (2.51 mmol, 1 equiv) 2b' and a stir-bar, and a
second round-bottom flask charged with a stir-bar were introduced into the glove box. 2b' was
dissolved with 50 mL dry THF (filtered on celite and dried over molecular sieves). To the RB flask
was added 0.844 g Copper(II) chloride (6.27 mmol, 2.5 equiv) and 20 mL of dry THF, forming a
suspension. The two flasks were both septum sealed and exported from the glove box. The Schlenk
flask was loaded into an acetone/dry ice bath stabilized at temperature -80 OC and connected to a
positive pressure of N2 from a Schlenk line. The RB flask was placed in a water/ice bath at
temperature 0 oC, adjacent to the Schlenk flask. Then, dropwise 3.0 mL of 2.1 M nBuLi (6.27 mmol,
2.5 equiv) was added to the Schlenk flask; the mixture was allowed to stir for 20 min until the
temperature of the acetone/dry ice bath had risen to -30 oC, at which point the reaction medium of
the Schlenk flask was transferred slowly to the stirring CuC12 suspension via cannula. The CuC12 went
into solution and rapidly became dark-green colored, and was allowed to stir for 10m. Afterward,
the green solution was concentrated in vacuo and re-diluted with 150 mL EtOAC. This solution was
washed twice by 150 mL 1 M HCI, and once by 100 mL brine - the dark color of the organic layer
vanished in the acid wash. The organic phase was collected, dried over Na 2 SO4, and stripped by
rotary evacuation. The crude material was then purified by chromatography on alumina with 2:1
-77-
CH2C12 :Hx-H as eluent. The product eluted later from the column and was identified as a large dot
with Rf ~ 0.05 on alumina TLC that appears bright blue when visualized with 210 nm light from a Hglamp. After chromatography, the purified material was recrystallized from hot MeOH. After allowing
the solution to cool at room temperature, the supernatant was decated. The product was isolated as
a near-white powder in 84% yield.
4b'. The procedure used for the hydrolysis of 3b' was analogous to that used for the hydrolysis of the
non-methoxy derivative; see procedure for 4b. On a scale of.238 g of 3b', 0.192 g of an off-white
precipitate was gathered from the frit after filtration, in overall 86% yield.
2w Dimethyl 1,1'-(2-(tert-butyldimethylsilyloxy)propane-1,3-diyl)bis(1H-indole-3carboxylate). To an oven-dried pear-shaped flask was added 2.00 g (11.42 mmol, 1 equiv) of methyl
1H-indole-3-carboxylate and a stir bar. The PS flask was subsequently introduced into a glove box, in
which 10 mL of dry DMF was added. In a separate vial 0.277 g (11.53 mmol, 1.01 equiv) of dry NaH
was weighed out and 10 mL of dry DMF was added to the vial to form a suspension. The NaH was
transfered to the PS flask containing the indole reactant as a suspension. After allowing all H2 to
expel from the PS Flask, it was septum sealed, exported from the glove box, and placed in an oil-bath
kept at the steady temperature of 95 OC. 1.88 g tert-butyl(1,3-dibromopropan-2-yloxy)dimethylsilane
(5.71 mmol, 0.500 equiv) was separately weighed out as a liquid in a vial, and dissolved in 5 mL DMF.
It was then added to the stirring reaction medium via syringe; an additional 2 mL of DMF was used to
rinse the vial, and these contents were also injected into the PS flask by syringe. The solution was
allowed to stir for 4 h, after which the reaction mixture was concentrated via rotary evacuation with
gentle heat applied to yield a brown residue. The residue was re-dissolved in 250 mL CH2C12, and
washed once by 150 mL of saturated NaHCO 3 and once by 150 mL brine. The organic phase was
collected, dried over Na2 SO4. The resulting material was purified by column chromatography on
-78-
alumina, using 3:1 CH2C12 :Hx-H as eluent. The product appears as the main dot on alumna TLC with
Rf - 0.80. After chromatography, 2w was isolated as colorless crystals in 58% yield.
3w. An oven-dried Schlenk flask, charged with 1.246 g (2.395 mmol, 1 equiv) 2w and a stir-bar, and
a second round-bottom flask charged with a stir-bar were introduced into the glove box. 10 was
dissolved with 20 mL dry THF (filtered on celite and dried over molecular sieves). To the RB flask
was added 0.796 g Copper(II) chloride (5.99 mmol, 2.5 equiv) and 20 mL of dry THF, forming a
suspension. The two flasks were both septum sealed and exported from the glove box. The Schlenk
flask was loaded into an acetone/dry ice bath stabilized at temperature -800C and connected to a
positive pressure of N2 from a Schlenk line. The RB flask was placed in a water/ice bath at
temperature 0 oC, adjacent to the Schlenk flask. Then, drop-wise 2.4 mL of 2.5 M nBuLi (5.99 mmol,
2.5 equiv) was added to the Schlenk flask; the mixture was allowed to stir for 10m, at which point the
reaction medium of the Schlenk flask was transferred slowly to the stirring CuC12 suspension via
cannula. The CuC12 went into solution and rapidly became dark-green colored, and was allowed to
stir for 10m. Afterward, the green solution was concentrated in vacuo and re-diluted with 150 mL
EtOAC. This solution was washed twice by 150 mL 1 M HC1, and once by 100 mL brine - the dark
color of the organic layer vanished in the acid wash. The organic phase was collected, dried over
Na2S0 4, and stripped by rotary evacuation to admit a brown powder. The crude material was
recrystallized from 15 mL hot MeOH. After allowing the solution to cool at room temperature, the
supernatant was decanted. The product was isolated as a near-white powder in 64% yield.
4w. A round bottom flask is filled with .643 g of 3w (1.240 mmol, 1 equiv) and a stirbar. The
material is solvated with 14 mL THF, and put under an atmosphere of N2 through a septum. 4 mL of
1.0 M tetrabutyl ammonium fluoride (3.270 mmol, 3 equiv) was added by syringe. The solution was
allowed to stir for a 10m; an immediate color change from colorless to green was observed upon
addition of tetrabutyl ammonium fluoride. 30 mL of H2 0 was added to the RBF, and the color quickly
-79-
vanished. The emulsion was poured into a separatory funnel, where 150 mL of EtOAC was
eventually added until all the organic material was dissolved. This layer was washed once with 150
mL H 20 and once with 150 mL brine. The organic phase was collected, dried over Na 2SO4, filtered,
and stripped via rotary evaporation. The crude material was recrystallized from 20 mL hot MeOH
and allowed to cool at room temperature for 30 min. The snow white powder was isolated via
filtration over a frit, furnishing the desilylated material in overall 84% yield.
Sw. 0.109 g of compound 4w (0.270 mmol, 1 equiv) was dissolved in 12 mL of dry THF inside a
round bottom flask charged with a stir bar in the glove box. In a separate flask, 0.150 mL of
phosphorous oxychloride POC13 (1.64 mmol, 6 equiv) was dissolved in 5 mL of dry THF. The flasks
were septum sealed and exported from the glove box. Then, 0.530 mL of anhydrous pyridine (6.60
mmol, 24 equiv) was added to the POC13 solution at 0 oC. The solution containing the bisindole
substrate was added to the Pyridine/POCls3 solution at 0 oC dropwise over the course of 2 min. The
solution was left to stir in the ice bath for 1 h, then the round bottom flask containing the reaction
medium was allowed to warm, and filtered through a fine frit. 20 mL of H20 was added to the filtrate,
and it was left stirring at ambient temperature. The filtrate was concentrated by rotary evaporation,
then diluted with 40 mL of 1 M HC1. The resulting solution was extracted twice with 50 mL of ethyl
acetate. The aqueous phase was stripped of liquids in vacuo, resulting in an off-white solid,
confirmed to be product in 75% yield.
6w. 80 mg of 5w was added to a round-bottom flask containing 4 mL DMSO, 0.8 mL 3 M KOH. The
resulting suspension was allowed to stir at 90 oC for 1 h, and eventually became homogeneous.
Afterwards, the solution was diluted with H 20 and acidified with glacial acetic acid, down to a
minimal pH of -3, then acidified further with 6 M HCI until a pH of -1. Slowly, precipitate formed
from the solution. The precipitate was obtained by vacuum filtration, and dried further by repeated
- 80 -
solvation in methanol and quick rotary evaporation to remove water. The dicarboxylic acid product
was obtained in quantitative yield.
2w'-6w'. The synthesis of the methoxylated derivative of 6w, 6w', was carried out using a set of
transformations identical to the non-methoxylated synthesis, except commencing with methyl 5methoxy-1H-indole-3-carboxylate in place of 1H-indole-3-carboxylate. Isolated yields for each of the
synthetic intermediates were: 2w', 43%; 3w', 47%; 4w', 84%; 5w', 98%; 6w', 84%.
-81-
IV-5. NMR spectra of Bisindoles (Section III)
C
C
C
C
oC C
CDC
CD
09,C
C
-82-
2a. 13C NMR spectrum
-700
600
500
-400
300
200
100
ll~~r.... .. . ..
... .... .LJ~I
.Y r ....... . .. .. I.~R
...............
I
"............
-0
.........
-100
150
ppm (tl)
100
50
ppm (fi)
1500
1000
500
0
150
ppm (fl)
100
100
ppm (tl)
50
I
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01
I
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(x)
wudd
loot
lost
PO~00
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loor
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150
ppm (fl)
100
50
80
ppm (fl)
70
60
50
40
150
ppm (fl)
100
50
100
ppm (fl)
50
4b. 13C NMR spectrum
-3000
- 2000
1000
-.I
-
- --
-
I
150
ppm (fl)
1
0
i
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100
I
I
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50
I
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ppm (ti)
70
60
50
40
30
20
2c. 13C NMR spectrum
-400
-300
200
-100
II
'Lr
l'l.
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]
'i
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rlr,-llr
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ppm (fl)
r
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100
1
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1
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r
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r
ppm
1000
100
ppm (fl)
50
-300
4c. 1H NMR spectrum
-250
200
-150
100
-50
A ;-y --
_joo
Y"
,,
0YY
CI
I
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100
I
-0
150
ppm (fl)
100
50
2b'. H NMRspectrum
.3000
2000
-1000
Sor
70
ppm (fl)
CY
60
50
40
30
2b'. 13C MR spectrum
-300
-250
200
-150
-100
50
-0
-50
a. I
ad91J
J
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150
ppm (fl)
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3b'. 1HNMRspectrum
3000
1000
750
ppm (fl)
100
ppm (fl)
50
3500
3000
2500
2000
-1500
-1000
-500
-0
-- 500
50
ppm (fl)
00
1000
150
ppm (fl)
100
50
0
3w. IH NMR spectrum
2500
-2000
- 1500
C
1000
500
0
1000C
-5000
150
ppm (fl)
100
50
0
80
ppm (fl)
70
60
50
40
30
150
ppm (fl)
100
50
Sw. 1H NMR spectrum
-
iLl
D
m
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80
rnnm Ifl
T
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5w. 31 P NMR spectrum
- 3500
- 3000
2500
2000
1500
1000
500
-0
-500
S
300
ppm (fl)
I
I
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200
100
.
I
0
.
I
-100
I
-200
80
ppm (fl)
70
60
50
40
30
Sw. 31 P NMR spectrum
-4000
3000
2000
1000
1.~.d.....
i..... ...I ...
1.L...
I
.
+_,......
.
I .4111 L
I_.LL
u.....
I
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300
ppm (fl)
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1
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100
'
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I
0
I'
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1
-200
I.
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2w'. 1H NMR spectrum
-2500
-2000
- 1500
- 1000
500
]ii
LYR)
0)o
YY-~~
I
ppm (fl)
L
II1
-0
yo
y
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150
ppm (fl
100
50
0
-3500
3w'. IH NMR spectrum
-3000
- 2500
- 2000
- 1500
-
1000
- 500
(z
y
80
ppm (fl)
1
00
-0
OCKo
L
y
Y W-
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70
60
50
CIA
Y
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T, :
30
20
10
00
3w'. 13C NMRspectrum
-5000
-4000
- 3000
- 2000
- 1000
]
-[
ii
...............
"'
I
I
ppm (fl)
I
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-.........
--
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1
0
1
Lr-
80
ppm (fl)
c
70
60
50
40
4w'. 13C NMR spectrum
-6000
-5000
-4000
-3000
- 2000
- 1000
-.-.
LI--.~.-~Y-I -IY- -L---.
~r ---L-Y --yl.~YI--~ -~.I -Y--Y-~
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ppm (fl)
[ --II------------ ~--lyl--L----~I---- I--~--~--'
'
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50
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1
I
I
I
I
I
-0
-- 1000
5w'. 1H NMR spectrum
-4000
-3000
- 2000
-1000
1'L
_.I.-
vS
80
ppm (fl)
m
a,
yO,
'" -~~-------~
INy
70
60
50
(W
r
40
('4 C)
-0
6000
5000
4000
-3000
-2000
S1000
-0
ppm (fl)
110
ppm (fl)
100
90
80
70
60
50
40
30
OWt. 13C NMR spectrum
I
- 2500
- 2000
1500
-1000
500
i.~J~M.iiLL.J.LM~ii ~
ppm (fl)
0
6w'. 31P NMR spectrum
-6000
- 5000
-4000
-3000
-
2000
-1000
r.,~u. u~l~r~-J.1. -L u l-rl-W I ~L~II*LY.LL.~W.
.~Ly
Jyr.LrLU
I~-II(I.III
L~~IYY-I-IY~rLUI~41LI(Y~ LILIIYPI II II~-ILr ~L~LY~LIY -0
- 1000
I
20
ppm (fl)
10
0
90
ppm (fl)
80
70
60
50
40
100
ppm (fl)
50
The Author.
Stephen D. Fried was born in Kansas City, Kansas
on 26 March 1987. Fascinated by mathematics at a
young age, and then by the sciences in secondary
school, he had formulated that he wanted to
become a molecular biologist because it appeared
to him that "all" the discovery left to be done was in
the life sciences.
In the September of 2005, he enrolled at the
Massachusetts Institute of Technology. Once at
MIT, he quickly changed his scientific interests
toward chemistry, and began working in the Nocera
Figure 16. Stephen looking pensive
laboratory. Initially inclined to be an organic
chemist, Stephen was exposed to a more
fundamental and quantitative description of Nature through an introductory
physical chemistry class in his junior year, and proceeded to pursue a second degree
in physics in his remaining three semesters.
His present research interest intersects the fields of inorganic chemistry, condensed
matter physics, and material science, with attention to elucidating mechanisms of
energy and electron transfer at the molecular and nanoscopic levels. By addressing
this fundamental question from a multidisciplinary perspective, Stephen's interest
targets novel applications to address challenges of energy generation, interconversion, and storage. Additional academic interests of his include linguistics and
medieval history.
In June 2009, he will graduate with degrees in Chemistry, Physics, and a minor in
History. A Hertz finalist and Phi Beta Kappa inductee, Stephen will commence Ph.D.
studies in the autumn of 2009 at Stanford University under the support of an NSF
Graduate Research Fellowship. He hopes to never leave academia, and become a
professor as well someday.
-126-