Site-selective arene C-H amination via photoredox catalysis

Article abstract of DOI:10.1126/science.aac9895

Over the past several decades, organometallic cross-coupling chemistry has developed into one of the most reliable approaches to assemble complex aromatic compounds from preoxidized starting materials. More recently, transition metal-catalyzed carbon-hydrogen activation has circumvented the need for preoxidized starting materials, but this approach is limited by a lack of practical amination protocols. Here, we present a blueprint for aromatic carbon-hydrogen functionalization via photoredox catalysis and describe the utility of this strategy for arene amination. An organic photoredox-based catalyst system, consisting of an acridinium photooxidant and a nitroxyl radical, promotes site-selective amination of a variety of simple and complex aromatics with heteroaromatic azoles of interest in pharmaceutical research. We also describe the atom-economical use of ammonia to form anilines, without the need for prefunctionalization of the aromatic component.

Full text of DOI:10.1126/science.aac9895

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effective sintering aid for solid-state reactive sintering. M.Sa.
measured proton concentration in cathode material. S.R.
contributed to the preparation of the pastes for the electrolytes
and cathode bones. A.A. participated in discussion and analysis
of the methane-fueled cell testing. J.T., R.O’H., and C.D. analyzed
all experimental data and wrote the paper.
ACKNOWLEDGMENTS
This work was supported by Advanced Research Projects
Agency–Energy (ARPA-E) for funding under the REBELS program
(award DE-AR0000493), the National Science Foundation
Materials Research Science and Engineering Centers program
under grant DMR-0820518, and the Petroleum Institute in Abu
Dhabi, United Arab Emirates. This work is related to U.S. Patent
application 62/101,285 (2015) and U.S. Patent application
14/621,091 (2015) filed by J. Tong et al. J.T. and R.O’H. developed
the intellectual concept, designed all the experiments, and
supervised this research. C.D. performed the fabrication and
testing experiments of PCFC single cells. M.Sh. synthesized and
tested the cathode materials. S.N. identified the copper oxide as an
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/349/6254/1321/suppl/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S24
Tables S1 and S2
References for Fig. 1, A and B
References (28–91)
21 April 2015; accepted 13 July 2015
Published online 23 July 2015
10.1126/science.aab3987
24. L. Yang et al., Science 326, 126–129 (2009).
ORGANIC CHEMISTRY
Taken together, this body of precedent research
illustrates a number of remaining challenges in
aryl C-H amination chemistry: (i) achievement of
site-selective addition; (ii) extension of the nitro-
gen coupling partner beyond amides and imides,
including the direct synthesis of primary anilines;
and (iii) achievement of atom-economical and mild
synthetic conditions. In this report, we describe
our efforts to develop a C-H amination method-
ology that addresses these limitations and demon-
strates the combination of organic photoredox
catalysis with nitroxyl radicals as co-catalysts.
We hypothesized that an arene cation radical
could serve as a key reactive intermediate in a
direct, intermolecular C-H aryl amination. We
believed that an amine could form s-adduct 2
with an arene cation radical 1, generated upon
photoinduced electron transfer (PET) from the
arene to an excited-state photoredox catalyst (cat*)
(Fig. 1) (17–21). The subsequent deprotonation of
distonic cation radical 2, followed by oxidative
aromatization of intermediate 3, would deliver
the desired aminated arene. As this process con-
stitutes a two-electron and two-proton loss, an
equivalent of a two-electron oxidant would be
required for each photocatalyst turnover. In addi-
tion to an earlier report of an intramolecular
cyclization initiated by PET (22), several recent
investigations suggested that such a process was
feasible. First, Yoshida and co-workers reported
the synthesis of aryl amines by means of elec-
trochemical oxidation (23–25). Essential to this
achievement was the use of protected amines to
insulate the C-N–coupled products from subse-
quent oxidative degradation. Accordingly, an addi-
tional synthetic step was required to liberate the
desired targets. Second, Fukuzumi and co-workers
studied the addition of bromide and fluoride
anions to arene cation radicals, generated upon
PET, via an organic photoredox catalyst (26, 27).
Dioxygen (O2) served as a terminal oxidant and
was believed to play a role in both the regener-
ation of the photoredox catalyst and the aroma-
tization to furnish the aryl halide.
Site-selective arene C-H amination
via photoredox catalysis
Nathan A. Romero, Kaila A. Margrey, Nicholas E. Tay, David A. Nicewicz*
Over the past several decades, organometallic cross-coupling chemistry has developed into one
of the most reliable approaches to assemble complex aromatic compounds from preoxidized
starting materials. More recently, transition metal–catalyzed carbon-hydrogen activation has
circumvented the need for preoxidized starting materials, but this approach is limited by a lack
of practical amination protocols. Here, we present a blueprint for aromatic carbon-hydrogen
functionalization via photoredox catalysis and describe the utility of this strategy for arene
amination. An organic photoredox-based catalyst system, consisting of an acridinium
photooxidant and a nitroxyl radical, promotes site-selective amination of a variety of simple
and complex aromatics with heteroaromatic azoles of interest in pharmaceutical research.
We also describe the atom-economical use of ammonia to form anilines, without the need for
prefunctionalization of the aromatic component.
he development of catalytic procedures for
the selective modification of carbon-hydrogen
(C-H) bonds carries the promise of stream-
lined and sustainable syntheses of high-
value chemicals. Direct transformation of
amines could be generated in a single step for
medicinal chemistry screening.
Many of the recent advances in aryl C-H ami-
nation have been propelled by the ability of
transition metals to activate C-H bonds. Although
a regioselective addition to an arene that lacks a
strong electronic or steric bias is an intrinsic
challenge of aryl C-H functionalization, a num-
ber of researchers, including Buchwald and co-
workers (7), Daugulis and co-workers (8), Shen
and co-workers (9), and Nakamura and co-workers
(10), have achieved orthoselective addition by rely-
ing on Lewis-basic substituents to direct the site of
metalation. Beyond transition metal–catalyzed
approaches, imidation of arenes and heteroarenes
has been achieved by Sanford and co-workers in a
photoredox mediated system (11), as well as by
Chang (12) and DeBoef (13) and their respective co-
workers, who employed PhI(OAc)2 as an oxidant
(Ph, phenyl; OAc, acetate). In these cases, regiose-
lectivity was modest at best. Of the intermolecular
C-H amination examples reported in the literature,
few operate with the arene as a limiting reagent.
Exceptional in this regard are the systems reported
in studies led by Ritter (14), Baran (15), and Itami
(16), yet each method appears to be exclusive to a
single nitrogen coupling partner.
T
aryl C-H bonds into carbon-carbon (C-C), carbon-
oxygen (C-O), and carbon-nitrogen (C-N) bonds
can provide efficient access to arenes with di-
verse structural properties (1, 2). In particular,
interest in aryl C-H amination (construction of a
C-N bond from a C-H bond) is driven by the
ubiquity of aryl C-N bonds in pharmaceuticals,
natural products, agrochemicals, pigments, and
optoelectronic materials. In contrast to the Buchwald-
Hartwig (3, 4) and Chan-Lam (5, 6) aminations,
which stand as the current preferred methods
for catalytic aryl C-N bond construction, a C-H
amination strategy could circumvent the need
for prior functionalization of the arene as halide,
triflate, or boronic acid. This synthetic advan-
tage is augmented by the application of C-H
amination to late-stage functionalization of syn-
thetic targets, wherein libraries of complex aryl
These studies lend support for the arene ami-
nation blueprint outlined in Fig. 1, and, given that
aerobic conditions have been used in previous oxi-
dative photoredox processes, O2 was an attractive
Department of Chemistry, University of North Carolina–
Chapel Hill, Chapel Hill, NC 27599-3290, USA.
*Corresponding author. E-mail: nicewicz@unc.edu
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Fig. 1. A blueprint for site-selective C-H amination of aromatics. LEDs, light-emitting diodes; hu, light.
Fig. 2. Reaction development.
(A) Catalyst optimization and
(B) the proposed mechanism.
Reactions run with 1.0 equivalent
of 4 and 2.0 equivalents of 5, unless
otherwise noted. E*red values for
A to C are given versus SCE (see
the supplementary materials for
details). BQ, 1,4-benzoquinone.
choice as a terminal oxidant and was our starting
point for this investigation.
In our initial screens for reactivity, we used
commercially available acridinium catalysts A
and B (Fig. 2, inset), as they have highly pos-
+2.20 and +2.09 V versus the saturated calomel
electrode (SCE), respectively] and are robust in
the presence of strong nucleophiles. We selected
pyrazole (5) as a representative nucleophile and
anisole (4) as the arene coupling partner (28).
Under the conditions given in Fig. 2A, but in the
absence of oxygen, little C-N–coupled arene ad-
duct (6a and 6b) was observed. However, when
the reaction was run under a balloon of O2, a
combined 47% yield of 6a and 6b was observed,
with good para:ortho selectivity (ratio of 6.7:1).
Subsequent first-pass optimization efforts produced
itive excited-state reduction potentials [E*red
=
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RESEARCH
| REPORTS
no gain in yield for the catalyst, concentration,
solvent, or other oxidants.
to detect catalyst A or B in crude proton nuclear
magnetic resonance (1H NMR) spectra, we ques-
tioned the stability of the catalyst under the re-
action conditions. Moreover, both anisole (4) and
acridinium are susceptible to degradation reac-
tions in the presence of oxygen-centered radicals
(29); we therefore surveyed a number of additives
that could mitigate any highly reactive radical in-
termediates, such as peroxyl radicals.
We found that 10 mol % 2,2,6,6-tetramethyl-
piperidine-1-oxyl (TEMPO) improved the yield of
6a and 6b to 65%. We also observed that the
remaining mass balance was almost entirely un-
reacted anisole. Increased equivalents of TEMPO
afforded a yield of 74% that decreased with
higher loadings.
This plateau in yield could have several causes.
First, aryl amine products 6a and 6b (irrevers-
ible half-peak potential, Ep/2 = +1.50 V versus
SCE) possess lower oxidation potentials than
anisole does (Ep/2 = +1.87 V versus SCE), and 6a
and 6b could competitively reduce excited-state
acridinium (cat+*), resulting in product inhibition.
Second, analysis of the reaction mixture revealed
that phenyl formate was the major byproduct, in-
dicating that, in addition to product inhibition,
side reactions of the arene reactant were prob-
lematic under these conditions. Third, after failing
As an additional measure to prolong the viabil-
ity of the acridinium catalyst, we modified the
acridinium structure to confer stability against
addition of nucleophiles or radicals (9-mesityl-3,6-
di-tert-butyl-10-phenylacridinium tetrafluoroborate,
C). The use of this catalyst provided the best re-
sults to date, producing compound 6 in 88% yield
after 20 hours. A 97% yield was achieved under an
atmosphere of air after irradiation for 3 days. The
use of immobilized TEMPO on polystyrene resulted
in a 65% yield of the aminated arene and facilitated
its recovery and reuse via simple filtration.
Fig. 3. Reaction scope for the C-H amination. Parenthetical ratios refer to para:ortho (p:o) selectivity for the given N-isomer. Reactions were run in 1,2-
dichloroethane (DCE) at 0.1 M concentration with respect to the arene limiting reagent.The asterisk indicates a reaction run with 2.0 equivalents of arene, 1.0
equivalent of amine, and 1.0 equivalent of TEMPO under an N2 atmosphere for 44 hours. The dagger indicates a reaction run under N2 with 1.0 equivalent of
TEMPO. Hex, hexyl group; Ac, acetyl group.
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The mechanism of this reaction is currently
the subject of detailed investigation. We believe
the role of TEMPO is to aromatize radical inter-
mediate 9 directly by H-atom abstraction (Fig.
2B). Alternatively, radical 9 could be trapped by
O2 to form 1,3-cyclohexadienyl peroxyl radical
10, from which internal elimination would yield
positions (32). For example, under the electro-
chemical oxidation conditions in (24), alkyl-
substituted arenes give rise to benzylic amination
over aryl amination. Our initial attempts to apply
the previously optimized conditions to the coup-
ling of pyrazole with mesitylene were hampered
by competitive benzylic oxidation to the aryl
aldehyde (table S2), a reactivity previously
documented in (33). Excluding O2 suppressed
benzylic oxidation and increasing the TEMPO
loading to 1.0 equivalent enabled the addition
of pyrazole to the aromatic ring of mesitylene, for-
ming 16 in excellent yield (82%). No products
resulting from benzylic oxidation were observed.
Likewise, m-xylene reacted under these conditions,
albeit in lower yields (36%); the remainder of
the mass balance was attributed to unreacted
starting material. Even modest yields are notable
in this context, given the oxidation potential of
m-xylene (Ep/2 = +2.28 V versus SCE) and the
excited-state reduction potential of catalyst C.
Considering the acidity of alkylbenzene cation
radicals [pKa [PhMe]+• = –20, where Ka is the acid
dissociation constant (34)], it is remarkable that
productive aryl C-H amination occurs for mesi-
tylene and m-xylene.
Azoles are a privileged structural unit in phar-
macologically active compounds (35, 36) and in
the architectures of transition metal–catalysts
and organocatalysts. Yet the most reliable meth-
ods for constructing aryl-azoles require at least
two synthetic steps. We found that a diverse range
of N-heterocyclic nucleophiles could be directly
coupled to an arene in our reaction protocol. In
addition to pyrazoles (27 to 29), we found that
1,2,3- and 1,2,4-triazoles (30, 32), tetrazole (31),
imidazole and benzimidazole (33 and 36), ben-
zotriazole (34), and tetrahydro-indazole (35) pro-
duced good to excellent yields of the C-N adducts
(53 to 85%). A di-Boc–protected adenine (Boc,
butoxycarbonyl) gave nearly quantitative yields
(99%) of purines (37) in a 1.1:1 N-regioisomeric
ratio.
To evaluate whether this catalyst system could
be applied to late-stage functionalization, we
tested the C-N bond–forming protocol with rep-
resentative druglike molecules, as shown in Fig. 3
(bottom). The successful coupling of Boc-histidine
methyl ester with 4 offers a new strategy for the
modification of biologically relevant structures
containing this amino acid. When reacted with
pyrazole, O-acetylcapsaicin, naproxen methyl
ester, and dihydroquinidine·trifluoroacetic acid
(DHQD·TFA) were transformed into single regio-
isomers of the adducts (38 to 41). Despite het-
eroatom substitution at the benzylic position, no
oxidation of the benzylic C-H bonds was ob-
served in either O-acetylcapsaicin or DHQD·TFA
in the reactions forming 39 and 41, respectively.
Likewise, naproxen methyl ester contains a sensi-
tive benzylic C-H bond that remained undisturbed
in the coupling reaction. These results demonstrate
the mildness and practicality of the protocol.
The regioselectivities observed in these trans-
formations are challenging to interpret, given
the diversity of substituents on the arene coup-
ling partner. Previous studies have found quali-
tative correlations between the observed site
selectivity and the lowest unoccupied molecular
orbital coefficients (23) or partial atomic charges
(26). The aforementioned work is consistent with
the expectation of nucleophilic addition to a cat-
ion radical at positions that afford a stabilized
radical; in arenes bearing a single substituent, ad-
dition at the ortho and para positions is favored
over meta-addition. Other differentiating factors,
such as steric effects, may be intertwined with
arene electronics, and future mechanistic studies
could clarify the key contributions to the regio-
selectivities observed.
•
product 11 and hydroperoxyl radical HO2 (30).
As proposed in (26), O2 can oxidize acridine rad-
ical Mes-Acr• (Mes, mesityl; Acr, acridinium), re-
generating acridinium Mes-Acr+ and superoxide
O2–•, although other putative intermediates might
be capable of catalyst turnover (e.g., HOO•)(Fig. 2B).
The strongly basic superoxide should deprotonate
intermediate 10, then undergo hydrogen atom
transfer with TEMPO-H, ultimately forming H2O2
and regenerating TEMPO. The decrease in un-
desired byproducts observed when TEMPO was
included is consistent with the proposed activity
of TEMPO-H, which is expected to scavenge re-
active oxygen-centered radicals, such as hydro-
•
peroxyl radical HO2 . Although the half-wave
redox potential of TEMPO [E1/2 (TEMPO•/
TEMPO+) = +0.62 V versus Ag/AgCl] (31) points
to the possibility of oxidization by cat+*, the use
of 20 mol % TEMPOnium-BF4 produced com-
parable results to TEMPO in the aryl amination
reaction (table S1). This suggests that a common
mechanistic intermediate is accessible—namely,
TEMPO—presumably generated by electron trans-
fer from cat• (E1/2 (cat+/cat•) = –0.47 to –0.58 V
versus SCE) to TEMPOnium. In the absence of
cat+, none of aryl amine 11 was generated with
20 mol % TEMPO, although trace product forma-
tion was detected when 20 mol % TEMPOnium-
BF4 was used and the acridinium photocatalyst
was omitted.
The optimized conditions were successfully ex-
tended to the coupling of pyrazole with a variety
of monosubstituted aromatics, including CH2OCH3
(MOM)–and tert-butyldimethylsilyl (TBS)–protected
phenol as well as biphenyl (12 to 15, 18; Fig. 3).
Halogenated anisole derivatives were excellent
substrates for the transformation and afforded
N-arylpyrazoles 19 and 20, with complete regio-
selectivity para to the methoxy substituent. Like-
wise, regiochemical discrimination is possible on
biaryls bearing electronically distinct aromatic
groups. Despite the availability of eight unique
aryl C-H bonds in 2-chloro-2'-methoxy-1,1'-biphenyl,
biaryl 21 was formed in 75% yield, with com-
pletely site-selective addition para to the methoxy
group, reflective of the electronic influences on
this manifold. Heterocycles bearing electron-
releasing substitution are competent substrates:
Dimethoxypyridine 22 and methoxyquinoline
23 were isolated in modest yields but as single
products. Heterocyclic motifs such as quinazoline
dione, 1-methyl indazole, and dihydrocoumarin
readily underwent C-H amination with pyrazole
to produce adducts 24 to 26. In all cases, a re-
gioselectivity ratio of >15:1 was observed.
Last, we explored whether anilines could be
forged directly from this catalytic sequence by
using either ammonia or an ammonium salt as
the nitrogen source. Traditionally, a nitration-
hydrogenation sequence is used to access anilines
directly. The latter protocol requires rigorous
Fig. 4. Synthesis of
anilines using ammo-
nium salt as ammo-
nia equivalent.
Reactions were run in
DCE and H2O (10:1) at
0.1 M concentration
with respect to the
arene limiting reagent.
One of the challenges associated with the oxi-
dative functionalization of arenes is the presence
of weak benzylic C-H bonds, particularly in arene
cation radicals, which have a documented pro-
pensity for H-atom and/or proton loss at these
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optimization to ensure safe dissipation of the
heat associated with the exothermic reaction
profile; potentially explosive intermediates and
toxic byproducts are also concerns. Only recently
has the Buchwald-Hartwig amination of aromatic
halides been accomplished with ammonia as the
nitrogen source (37). A C-H amination protocol of
benzene with ammonia, developed by DuPont,
uses a NiO-ZrO2 catalyst system at 350°C and 300
to 400 atm, producing aniline in a 14% maximum
yield (38, 39).
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After screening a variety of commercially available
ACKNOWLEDGMENTS
–
ammonium salts such as H4N+OAc–, H4N+HCO3 ,
Financial support was provided by the David and Lucile Packard
Foundation, Merck, and an Amgen Young Investigator Award.
N.A.R is grateful for an NSF Graduate Fellowship, and K.A.M. was
supported by a Francis Preston Venable Graduate Fellowship.
A provisional patent has been filed on the methods presented here
(U.S. patent application no. 62/170,632).
and (H4N+)2CO32–, we found that ammonium
carbamate (H4N+H2NCO2–) was best suited for
this role (table S3 and supplementary materials).
This benchtop-stable solid salt is less costly on a
molar basis than liquid ammonia. Using 4.0
equivalents of ammonium carbamate with anis-
ole, under catalytic conditions nearly identical to
those applied to azoles, resulted in the formation
of a 1.6:1 mixture of para- and ortho-anisidine in
59% isolated yield (42; Fig. 4).
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/349/6254/1326/suppl/DC1
Materials and Methods
Tables S1 to S4
References (40–73)
NMR Spectra
The scope of the aniline-forming reaction was
similar to the azole-coupling transformations. Pro-
tected phenols (43 to 45), haloarenes (47), and ni-
trogen heteroaromatics such as N-methylindazole
(48) and 6-methoxyquinoline (49) were aminated
under this protocol, albeit with modest regio-
selectivities in the case of the monosubstituted
aromatics.
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9 July 2015; accepted 19 August 2015
10.1126/science.aac9895
MINERAL SURFACES
Overall, these C-N bond–forming reactions are
powerful tools for the synthesis of complex aro-
matics using an organic photooxidant and nitroxyl
radical catalyst system. From the substrate scope
investigation, it is clear that free alcohols, esters,
silyl ethers, halides, amides, alkenes, and pro-
tected amines are all compatible functionalities.
The mildness of this protocol makes it appealing
for a variety of applications. Moreover, we antic-
ipate that this general method for the activation
of arenes will result in the development of ad-
ditional transformations.
X-ray–driven reaction front dynamics
at calcite-water interfaces
Nouamane Laanait,1,2*† Erika B. R. Callagon,2,3 Zhan Zhang,4 Neil C. Sturchio,5
Sang Soo Lee,1 Paul Fenter1*
The interface between minerals and aqueous solutions hosts globally important biogeochemical
processes such as the growth and dissolution of carbonate minerals. Understanding such
processes requires spatially and temporally resolved observations and experimental controls
that precisely manipulate the interfacial thermodynamic state. Using the intense radiation fields
of a focused synchrotron x-ray beam, we drove dissolution at the calcite/water interface and
simultaneously probed the dynamics of the propagating reaction fronts using surface x-ray
microscopy. Evolving surface structures were controlled by the time-dependent solution
composition, as characterized by a kinetic reaction model. At extreme disequilibria, we observed
the onset of reaction front instabilities with velocities of > 30 nanometers per second.
These instabilities serve as a signature of transport-limited dissolution of calcite under extreme
disequilibrium.
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alcium carbonate precipitates abiotically
and is synthesized by living organisms
into complex and functional biomineral
architectures (1). Combined, calcium carbon-
ate minerals constitute a major fraction of
Earth’s upper crust in the form of carbonate rocks
(2). Characterizing the rapidly evolving morphol-
ogy of calcium carbonate during growth (3, 4) and
dissolution (5, 6) is central to both a fundamental
understanding of its reactivity and manipulation of
its versatile functionality. The morphology of cal-
cium carbonate phases can be imaged in situ with
electron (7, 8) and x-ray microscopies; however, the
large radiation doses deposited by these probes can
substantially alter the state of the system (9).
We used a focused x-ray beam to both observe
and drive dissolution in a quantifiable manner
(10). The synchrotron x-ray beam induces acidi-
fication and depletion of carbonate ions within
the solution, which controlled the interfacial
C
1Chemical Sciences and Engineering Division, Argonne
National Laboratory, Argonne, IL, USA. 2Center for
Nanophase Materials Sciences, Oak Ridge National
Laboratory, Oak Ridge, TN, USA. 3Department of Earth and
Environmental Sciences, University of Illinois at Chicago,
Chicago, IL, USA. 4X-ray Science Division, Argonne National
Laboratory, Argonne, IL, USA. 5Department of Geological
Sciences, University of Delaware, Newark, DE, USA.
*Corresponding author. E-mail: laanaitn@ornl.gov (N.L.);
fenter@anl.gov (P.F.) †Present address: Center for Nanophase
Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
1330 18 SEPTEMBER 2015 • VOL 349 ISSUE 6254
sciencemag.org SCIENCE

Site-selective arene C-H amination via photoredox catalysis
Nathan A. Romero et al.
Science 349, 1326 (2015);
DOI: 10.1126/science.aac9895
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