Safe and Selective Nitro Group Reductions Catalyzed by Sustainable and Recyclable Fe/ppm Pd Nanoparticles in Water at Room Temperature

Article abstract of DOI:10.1002/anie.201604026

As a result of a unique synergy between ligand-free Fe/ppm Pd nanoparticles and PEG-containing designer surfactants, a facile and selective reduction of nitro-containing aromatics and heteroaromatics can be effected in water at room temperature in the presence of NaBH₄. This new nanotechnology involves low catalyst loadings, is highly chemoselective, and tolerates a wide variety of functional groups. The process, which includes recycling of the entire aqueous medium, offers a general, environmentally responsible, and notably safe approach to highly valued reductions of nitro-containing compounds.

Full text of DOI:10.1002/anie.201604026

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604026
German Edition: DOI: 10.1002/ange.201604026
Green Chemistry
Safe and Selective Nitro Group Reductions Catalyzed by Sustainable
and Recyclable Fe/ppm Pd Nanoparticles in Water at Room
Temperature
Jie Feng, Sachin Handa,* Fabrice Gallou, and Bruce H. Lipshutz*
Abstract: As a result of a unique synergy between ligand-free
Fe/ppm Pd nanoparticles and PEG-containing designer sur-
factants, a facile and selective reduction of nitro-containing
aromatics and heteroaromatics can be effected in water at room
temperature in the presence of NaBH4. This new nanotechnol-
ogy involves low catalyst loadings, is highly chemoselective,
and tolerates a wide variety of functional groups. The process,
which includes recycling of the entire aqueous medium, offers
a general, environmentally responsible, and notably safe
approach to highly valued reductions of nitro-containing
compounds.
A
romatic and heteroaromatic amines represent a class of
indispensible intermediates in the course of preparing fine
chemicals, biochemicals, and pharmaceuticals.[1] While
numerous synthetic pathways to generate such species exist,
perhaps the most prominent among them relies on hydro-
Scheme 1. Strategies towards reductions of nitro groups.
genation of nitro-containing compounds[2] and catalytic C N
À
bond-forming processes.[3] Hydrogenations typically depend
upon well-developed precious-metal-catalyzed reductions
(e.g., Pd,[4] Au,[5] Ru,[6] and alloys).[7] Alternatively, earth-
abundant metal-mediated reductions have also been de-
scribed using Zn,[8] Co,[9] Ni,[10] and Fe.[11]
on homogeneous conditions, although high catalyst loadings,
excess reducing agent, and limited substrate scope character-
ize these protocols. More recently, Beller and co-workers
have presented a number of very efficient, heterogeneous
nanoscale iron-oxide-based net reductions under reaction
conditions which involve either H2 at 50 bar, N2H4·H2O, or
HCOOH/Et3N as the hydrogen source.[11i–k] Energy-intensive
conditions (8008C) may represent an impediment to reagent
preparation, while the need for elevated reaction temper-
atures may place limitations on potential applications to
otherwise highly functionalized, sensitive molecules. Reac-
tion rates can also be a major factor, especially with processes
at scale where time in the kettle must be minimized for
effective use of a companyꢀs assets.
From an environmental perspective, use of either palla-
dium or iron catalysis, to date, involves use of organic
solvents. Water-miscible reaction media, such as commonly
used THF, can lead to large volumes of organic waste, and
even larger amounts of waste water streams. Thus, an
opportunity remains for new technology which takes these
important issues into consideration, thus providing a solution
that offers: simple reagent formation, broad substrate scope,
low catalyst loadings, short reaction times, high efficiency,
ambient temperature conditions, reaction medium recycla-
bility, and the elimination of organic solvents. Herein we
describe a new reagent and procedure which accomplishes all
of these goals and results in a safe reduction protocol.
In our previous work,[12] it was found that commercial
sources of FeCl3 naturally contain varying levels of palladium.
FeCl3 containing trace amounts of palladium, or FeCl3 doped
Palladium-catalyzed hydrogenation of a nitro group is
among the most widely used methods. Development of highly
active and reusable palladium catalysts remains an active area
of research for that transformation.[4a] Nonetheless, the levels
of palladium involved may lead to contamination of the
product, and various reaction parameters associated with its
use (e.g., the solvent, etc.) may raise environmental concerns.
Alternative, environmentally benign catalysts based on iron,
in particular, make an ideal choice for hydrogenations of
a nitro group. Early work in this area focused on stoichio-
metric iron-mediated reductions of nitro compounds under
aqueous acidic conditions (Scheme 1).[11b,e] Subsequent
reports by Thomas and co-workers, and others[11d,g,h] focused
[*] J. Feng, Dr. S. Handa, Prof. Dr. B. H. Lipshutz
Dept. of Chemistry and Biochemistry, University of California Santa
Barbara, Santa Barbara, CA 93106 (USA)
E-mail: shanda@chem.ucsb.edu
lipshutz@chem.ucsb.edu
J. Feng
College of Chemical Engineering, Nanjing University of Science &
Technology, Nanjing 210094 (P.R. China)
Dr. F. Gallou
Novartis Pharma, Basel (Switzerland)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604026.
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with 320 ppm Pd(OAc)2, when processed into nanoparticles
(NPs) readily catalyze Suzuki–Miyaura cross-couplings in
water under very mild reaction conditions.[12,13] Key to this
discovery was the use of aqueous nanomicelles composed of
our designer surfactant TPGS-750-M. These nanoparticles
serve as reaction solvent, and by virtue of the MPEG
contained therein, aggregate around the Fe/ppm Pd NPs,
thereby delivering a substrate to the catalyst. Their content,
aside from greater than 320 ppm palladium, includes an equal
amount of ligand (SPhos), which was crucial in supporting
catalyst activity. However, they are inactive towards reduc-
tions of nitro groups.
By modifying the composition of these Fe/ppm Pd NPs,
new NPs can be quickly generated by an even simpler
protocol. Reduction of commercially available FeCl3 (e.g.,
Sigma–Aldrich, 97%), doped with only 80 ppm (0.008 mol%)
Pd(OAc)2,[14] with MeMgCl (1 equiv) in THF at room
temperature, followed by quenching with wet pentanes and
then triturating with (additional) pentanes affords the desired
NPs. A ligand is not required for either NP activity or stability,
however, THF as a solvent is crucial for optimal activity. No
reaction is observed with the corresponding NPs prepared
from FeCl3 in the absence of Pd(OAc)2. The nanoparticles can
be either made in situ and used directly, or isolated and stored
for at least a month at ambient temperatures. They are well
dispersed in water, forming about 3 nm spherical particles
(Figure 1, left). These Fe/ppm Pd nanoparticles were found to
contain THF (Figure 1, right), albeit in bound form, as was
Figure 2. Influence of the surfactant on nitro group reductions of A, B,
and C.
even under prolonged reaction times (see the Supporting
Information).
À
evident from peak broadening in the C H stretching vibra-
tion at 3000–3500 cmÀ1 (see the Supporting Information).
Analysis by XPS indicates that the content of iron is about
8.6%.
Further screening focused on the stoichiometric source of
hydrogen. Inexpensive sodium borohydride was quickly
identified as the reagent of choice (see the Supporting
Information). The loading of NaBH4 in the range of 1.0–
3.0 equivalents is sufficient, as the dihydrogen released has far
greater dissolution in organic media relative to water,[15]
hence, higher concentrations of H2 should be present inside
the nanomicelles compared to the surrounding aqueous
medium.
Following optimization, several substrates were treated
with Fe/ppm Pd NPs to assess the generality and scope of this
technology (Table 1). Several nitroarenes with substituents
such as chloro, bromo, cyano, ester, and methylmercapto
showed good tolerance based on yields of the isolated and
desired amino derivatives. Remarkably, 4-nitrobenzoic acid
was successfully reduced (product 4), and is a highly chal-
lenging example of such a reduction in the presence of a free
carboxylic acid. By contrast, competitive side reactions led to
a decrease in yield in the case of 1-iodo-4-nitrobenzene
(product 7). The reduction is also amenable to nitroarenes
bearing other valuable substituents (CF3, F, CN, OH, etc.).
Sterically demanding substrates, such as those leading to
products 9 and 17, required prolonged reaction times relative
to the more typical 2–6 hours. Sites of unsaturation were also
Figure 1. TEM analyses and IR spectra of THF-bound Fe/ppm Pd
nanoparticles (NPs).
The presence of a surfactant is crucial for the observed
reactivity. That is, it provides both the hydrophobic inner core
for substrate binding, as well as substrate delivery based on
the MPEG present in each molecule. Screening of surfactants
using three different substrates identified TPGS-750-M
(2 wt%) as the preferred amphiphile in water (Figure 2).
Ionic surfactants such as SDS proved to be less effective. The
background reaction in water led to low levels of conversion
ꢀ
=
well tolerated (e.g., CN, RCOR’, C C, C C). Several hetero-
cycles containing nitro residues, likewise, proved to be
amenable (products 11, 15, 19, 20, 22–25). Aliphatic nitro
compounds were briefly examined, for example, ethyl 2-
nitropropanoate and 1, 2-dimethoxy-4-(2-nitroethyl)benzene.
These could also be smoothly converted into the correspond-
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Table 1: Representative reductions of nitro-group-containing educts.[a,b]
ing amines in satisfactory yields (see the Supporting Infor-
mation).
Several products reflecting potential interest from the
pharmaceutical perspective, that is, reductions of nitro-con-
taining species which may lead to either bioactive or drug-like
fragments, using low levels of metal-based reagents, are also
illustrated in Table 1 (29–32, 35, 36). For example, a multistep
synthesis of an intermediate en route to a potential measles
virus inhibitor[16] (32) was prepared by a four-step synthesis,
starting with a dinitro-substituted benzoic acid ester. Impor-
tantly, the residual palladium content in several of the amino-
containing products (e.g., 23, 30) was below 1 ppm in all cases.
The opportunity to effect tandem reactions based on
formation of amines, given the widespread applicability of
nanomicelles composed of TPGS-750-M in water, is illus-
trated in Scheme 2. Thus, a newly formed aniline could
Scheme 2. Nitro group reduction/amine protection in situ. Alloc=
allyloxycarbonyl, Boc=tert-butoxyccarbonyl.
smoothly be converted into its corresponding carbamate
derivative, including derivatization with standard protecting
groups such as Boc (37) Alloc (38), and the bis-proteced
amine 39, all in a one-pot process.
A nitro group reduction can also serve as the precursor
step to other useful secondary reactions. For example,
benzene-1,2-diamine 40 is produced from 1,2-dinitrobenzene,
which can be converted, by oxidative cyclization in situ, into
the benzimidazole 41 in excellent overall yield. (Scheme 3).
Scheme 3. One-pot nitro group reduction/oxidative cyclization.
Another major feature associated with this protocol is the
opportunity to recycle the aqueous reaction mixture. Once
a reduction is complete, in-flask extraction with minimum
amounts of a single organic solvent (e.g., EtOAc) allows for
isolation and purification of the desired product. Adjustment
of the pH to 7 with concentrated HCl, along with addition of
fresh NaBH4, leads to an active catalyst ready for re-
introduction of a nitroarene (see the Supporting Informa-
tion).
[a] Unless otherwise noted, reaction conditions were as follows: nitro
compound (0.5 mmol, 1 equiv), Fe/ppm Pd nanoparticles (6 mg),
NaBH4 (0.75–3.0 mmol, 1.5–3.0 equiv), 2 wt% TPGS-750-M/H2O
(1 mL). Yields are those of the isolated products. [b] Iron nanoparticles
(12 mg, 3.6%). [c] Using standardized Fe/ppm Pd (80 ppm) nano-
particles. [d] NaBH4 (0.55 mmol, 1.1 equiv). [e] NaBH4 (1.5 mmol,
3 equiv). [f] Iron nanoparticles (12 mg), NaBH4 (1.5 mmol, 3 equiv),
additional 0.1 mL THF. Bn=benzyl.
Two multistep, one-pot sequences, each involving a nitro
group reduction, are shown in Scheme 4, thus highlighting the
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and not water.[20] However, the potential interaction between
palladium and iron remains unclear, as without the iron NPs,
80 ppm palladium is insufficient to effect reduction to any
degree. Based on the observed chemoselectivity and func-
tional-group compatibility, the iron NP lattice may be crucial
in dispersing the ppm level of palladium present, thus leading
to highly active and efficient nanoparticles and avoiding high
aggregation states potentially formed during NP preparation.
In summary, a robust technology has been developed and
allows chemoselective, general, and efficient reductions of
nitro compounds in water at ambient temperatures. The
interaction of mixed metal nanoparticles containing iron and
ppm levels of palladium matched to surfactant-based nano-
micelles accounts for the exceptionally mild reaction profile,
unmatched by current literature procedures. Moreover, the
soon to be commercially available reagent, Fe/ppm Pd NPs,[21]
offers unique opportunities for multicomponent reactions run
in a single-pot operation, while the aqueous medium can
recycled, thus leading overall to environmentally responsible
chemistry.
Scheme 4. Sequential one-pot reactions and associated E Factors.
dramatic reduction of organic waste using micellar catalysis.
The overall E Factors,[17] based on utilization of organic
solvents (for extraction) are only 5–6, or 8–13 if water is
included. These values are quite low relative to existing
literature procedures, as well as those characteristic of the fine
chemicals (5–25) and pharmaceutical areas (25–100).[18] Both
reactions (Scheme 4a,b) involve a subsequent amidation step,
likewise, done in water.[19] The three-step sequence beginning
with 1-bromo-4-nitrobenzene 44 leads to the complex biaryl
45 in good overall yield and, again, with relatively little
organic waste.
Mechanistically, such nitro group reductions may follow
along classical lines, involving a palladium hydride species.
Initial release of H2 from NaBH4 upon contact with water,
should populate inside the nanomicelles, thus leading to
palladium hydride on the surface of these iron NPs
(Scheme 5). The interaction with nanomicelles housing the
Acknowledgements
We warmly thank Novartis and the Chinese Scholarship
Council (File No. 201406840011) for financial support of this
work.
Keywords: green chemistry · micelles · nanoparticles ·
reduction · water chemistry
[1] a) R. S. Downing, P. J. Kunkeler, H. Bekkum, Catal. Today 1997,
37, 121; b) N. Ono, The Nitro Group in Organic Synthesis, Wiley-
VCH, New York, 2001.
[2] S. Nishimura, Handbook of Heterogeneous Hydrogenation of
Organic Synthesis, Wiley, New York, 2001.
[3] For selected reviews see: a) J. F. Hartwig, Acc. Chem. Res. 1998,
31, 852; b) J. F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046;
Angew. Chem. 1998, 110, 2154.
[4] For selected recent references see: a) E. Negishi in Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 2; b) J.
Tuteja, S. Nishimura, K. Ebitani, RSC Adv. 2014, 4, 38241; c) P.
Wang, H. Liu, J. Niu, R. Li, J. Ma, Catal. Sci. Technol. 2014, 4,
1333; d) Y. M. Yamada, Y. Yuyama, T. Sato, S. Fujikawa, Y.
Uozumi, Angew. Chem. Int. Ed. 2014, 53, 127; Angew. Chem.
2014, 126, 131; e) H. Choudhary, S. Nishimura, K. Ebitani, J.
Mater. Chem. A 2014, 2, 18687; f) L. Li, H. Zhao, J. Wang, R.
Wang, ACS Nano 2014, 8, 5352.
[5] a) Q. Ge, J. Ran, L. Wu, T. Xu, J. Appl. Polym. Sci. 2015, 132,
42005; b) X. Liu, H. Q. Li, S. Ye, Y. M. Liu, H. Y. He, Y. Cao,
Angew. Chem. Int. Ed. 2014, 53, 7624; Angew. Chem. 2014, 126,
7754.
Scheme 5. Proposed mechanism for nitro group reductions in water.
[6] For an example, see: S. G. Oh, V. Mishra, J. K. Cho, B.-J. Kim,
H. S. Kim, Y.-W. Suh, H. Lee, H. S. Park, Y. J. Kim, Catal.
Commun. 2014, 43, 79.
[7] a) S. Sabater, J. A. Mata, E. Peris, ACS Catal. 2014, 4, 2038; b) H.
Gçksu, S. F. Ho, ꢁ. Metin, K. Korkmaz, A. Mendoza Garcia,
M. S. Gꢂltekin, S. Sun, ACS Catal. 2014, 4, 1777; c) S. Lihama, S.
Furukawa, T. Komatsu, ACS Catal. 2016, 6, 742.
nitro-group-containing substrate is likely given the precedent
associated with palladium-catalyzed Lindlar reductions using
the same source of hydrogen.[20] Sequential nitro reduction
should proceed, therefore, via intermediate nitroso and
hydroxylamines. It is assumed at this stage that the source
of hydrogen forming the amine derives from the reductant,
[8] S. M. Kelly, B. H. Lipshutz, Org. Lett. 2014, 16, 98.
4
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These are not the final page numbers!

Angewandte
Communications
Chemie
[9] Z. Zhao, H. Yang, Y. Li, X. Guo, Green Chem. 2014, 16, 1274.
[13] B. H. Lipshutz, S. Ghorai, Aldrichimica Acta 2008, 41, 59.
[10] For selected recent references see: a) V. M. Mokhov, Y. V.
Popov, D. N. Nebykov, Russ. J. Gen. Chem. 2014, 84, 1515; b) F.
Zamani, S. Kianpour, Catal. Commun. 2014, 45, 1; c) P. S.
Rathore, R. Patidar, T. Shripathi, S. Thakore, Catal. Sci. Technol.
2015, 5, 286; d) R. J. Kalbasi, F. Zamani, RSC Adv. 2014, 4, 7444.
[11] For selected recent references see: a) G. Gao, Y. Tao, J. Jiang,
Green Chem. 2008, 10, 439; b) R. Dey, N. Mukherjee, S.
Ahammed, B. C. Ranu, Chem. Commun. 2012, 48, 7982;
c) M. M. Moghaddam, B. Pieber, T. Glasnov, C. O. Kappe,
ChemSusChem 2014, 7, 3122; d) A. J. MacNair, M. M. Tran, J. E.
Nelson, G. U. Sloan, A. Ironmonger, S. P. Thomas, Org. Biomol.
Chem. 2014, 12, 5082; e) L. Wang, P. Li, Z. Wu, J. Yan, M. Wang,
Y. Ding, Synthesis 2003, 2001; f) X. Gu, Z. Sun, S. Wu, W. Qi, H.
Wang, X. Xu, D. Su, Chem. Commun. 2013, 49, 10088; g) L.
Pehlivan, E. Mꢃtay, S. Laval, W. Dayoub, P. Demonchaux, G.
Mignani, M. Lemaire, Tetrahedron Lett. 2010, 51, 1939; h) K.
Junge, B. Wendt, N. Shaikh, M. Beller, Chem. Commun. 2010, 46,
1769; i) R. V. Jagadeesh, G. Wienhofer, F. A. Westerhaus, A. E.
Surkus, M. M. Pohl, H. Junge, K. Junge, M. Beller, Chem.
Commun. 2011, 47, 10972; j) R. V. Jagadeesh, A. E. Surkus, H.
Junge, M. M. Pohl, J. Radnik, J. Rabeah, H. Huan, V. Schune-
mann, A. Bruckner, M. Beller, Science 2013, 342, 1073; k) R. V.
Jagadeesh, K. Natte, H. Junge, M. Beller, ACS Catal. 2015, 5,
1526; l) C. Wang, R. Ciganda, L. Salmon, D. Gregurec, J.
Irigoyen, S. Moya, J. Ruiz, D. Astruc, Angew. Chem. Int. Ed.
2016, 55, 3091; Angew. Chem. 2016, 128, 3143.
[14] a) K. Koide in New Trends in Cross-Couplings: Theory and
Applications, RCS Catalysis Series (Ed.: T. Colacot), 2014, pp.
779 – 810; b) For insight regarding the true nature of Pd(OAc)2,
see: W. A. Carole, J. Bradley, M. Sarwar, T. J. Colacot, Org. Lett.
2015, 17, 5472; c) P. G. Gildner, T. J. Colacot, Organometallics
2015, 34, 5497.
[15] a) C. L. Young, Hydrogen and Deuterium, Vol. 5/6 (Ed.: IUPAC
Solubility Data Series), Pergamon, Oxford, 1981; For a recent
example of using NaBH4 in water, see W.-G. Jia, H. Zhang, T.
Zhang, D. Xie, S. Ling, E.-H. Sheng, Organometallics 2016, 35,
503.
[16] A. Sun, A. Prussia, W. Zhan, E. E. Murray, J. Doyle, L.-T. Cheng,
J.-J. Yoon, E. V. Radchenko, V. A. Palyulin, R. W. Compans,
D. C. Liotta, R. K. Plemper, J. P. Snyder, J. Med. Chem. 2006, 49,
5080.
[17] R. A. Sheldon, Green Chem. 2007, 9, 1273.
[18] B. H. Lipshutz, N. A. Isley, J. C. Fennewald, E. D. Slack, Angew.
Chem. Int. Ed. 2013, 52, 10952; Angew. Chem. 2013, 125, 11156.
[19] C. M. Gabriel, M. Keener, F. Gallou, B. H. Lipshutz, Org. Lett.
2015, 17, 3968. See also, M. Parmentier, M. K. Wagner, K.
Magra, F. Gallou, Org. Proc. Res. Dev., DOI: 10.1021/
acs.oprd.6b00133.
[20] E. D. Slack, C. M. Gabriel, B. H. Lipshutz, Angew. Chem. Int.
Ed. 2014, 53, 14051; Angew. Chem. 2014, 126, 14275.
[21] Sigma – Aldrich catalog number 809330.
[12] A similar preparation of Fe/ppm Pd nanoparticles has been
described in our previous work. In this study, however, the NPs
do not require the presence of any ligand, and involve far less Pd
(80 vs. 320 ppm). See: S. Handa, Y. Wang, F. Gallou, B. H.
Lipshutz, Science 2015, 349, 1087.
Received: April 26, 2016
Revised: May 17, 2016
Published online: && &&, &&&&
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Communications
Green Chemistry
By design: As a result of a unique synergy
between ligand-free Fe/ppm Pd nano-
particles and PEG-containing designer
surfactants, a facile and selective reduc-
tion of nitro-containing (hetero)aromat-
ics by NaBH4 can be effected in water at
room temperature. The process offers
a general, environmentally responsible,
and notably safe approach to highly
valued reductions of nitro-containing
compounds.
J. Feng, S. Handa,* F. Gallou,
B. H. Lipshutz*
&&&& — &&&&
Safe and Selective Nitro Group
Reductions Catalyzed by Sustainable and
Recyclable Fe/ppm Pd Nanoparticles in
Water at Room Temperature
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!