Platinum-Catalyzed, Terminal-Selective C(sp3)-H Oxidation of Aliphatic Amines

Article abstract of DOI:10.1021/jacs.5b09099

This Communication describes the terminal-selective, Pt-catalyzed C(sp³)-H oxidation of aliphatic amines without the requirement for directing groups. CuCl₂ is employed as a stoichiometric oxidant, and the reactions proceed in high yield at Pt loadings as low as 1 mol%. These transformations are conducted in the presence of sulfuric acid, which reacts with the amine substrates in situ to form ammonium salts. We propose that protonation of the amine serves at least three important roles: (i) it renders the substrates soluble in the aqueous reaction medium; (ii) it limits binding of the amine nitrogen to Pt or Cu; and (iii) it electronically deactivates the C-H bonds proximal to the nitrogen center. We demonstrate that this strategy is effective for the terminal-selective C(sp³)-H oxidation of a variety of primary, secondary, and tertiary amines.

Full text of DOI:10.1021/jacs.5b09099

Communication
pubs.acs.org/JACS
Platinum-Catalyzed, Terminal-Selective C(sp3)−H Oxidation of
Aliphatic Amines
Melissa Lee and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
directing group.7c,10,11 We sought to utilize Pt catalysis to
ABSTRACT: This Communication describes the termi-
nal-selective, Pt-catalyzed C(sp3)−H oxidation of aliphatic
amines without the requirement for directing groups.
CuCl2 is employed as a stoichiometric oxidant, and the
reactions proceed in high yield at Pt loadings as low as 1
mol%. These transformations are conducted in the
presence of sulfuric acid, which reacts with the amine
substrates in situ to form ammonium salts. We propose
that protonation of the amine serves at least three
important roles: (i) it renders the substrates soluble in
the aqueous reaction medium; (ii) it limits binding of the
amine nitrogen to Pt or Cu; and (iii) it electronically
deactivates the C−H bonds proximal to the nitrogen
center. We demonstrate that this strategy is effective for
the terminal-selective C(sp3)−H oxidation of a variety of
primary, secondary, and tertiary amines.
achieve complementary reactivity, namely, terminal-selective
C−H functionalization at sites remote to nitrogen.12
We hypothesized that terminal-selective, Pt-catalyzed C−H
oxidation would be enabled by protonation of the amine
substrates (eq 1). The formation of ammonium salts would
address two of the existing challenges of Shilov catalysis. First,
quaternization should render the substrates water-soluble.
Second, the inductive electron-withdrawing effect of the
ammonium cation13 is expected to electronically deactivate
C−H sites proximal to nitrogen, thereby enhancing selectivity
for remote 1° C(sp3)−H bonds.14 In addition, we sought to
leverage prior work by Sames7c and Sen7d demonstrating that
CuII salts can be used as oxidants for Shilov-type reactions in
place of costly K2PtCl6.15 Our protonation strategy is also
crucial in this context, since unprotonated amines could
potentially undergo undesired side reactions with the CuII
oxidant.16
Our initial studies focused on the K2PtCl4-catalyzed C−H
hydroxylation of dipropylamine, which was protonated in situ
with H2SO4. We started with traditional Shilov conditions,
using 10 mol% of K2PtCl4, 1 equiv of K2PtCl6 as the terminal
oxidant (and limiting reagent), and 2 equiv of the amine H2SO4
salt at 120 °C. As shown in Table 1, entry 1, these conditions
afforded the C(sp3)−H hydroxylation product with high
terminal selectivity (>10:1 ratio of 1 to 1a) but only modest
yield (36%) over 48 h. Changing the terminal oxidant to CuCl2
under otherwise analogous conditions provided an enhanced
yield (66%), while maintaining high selectivity (>10:1; entry 2).
Increasing the temperature to 150 °C afforded a similar yield
(63%) over 30 h (entry 3). At this temperature, the catalyst
loading could be dropped to 1 mol%, with minimal impact on
the yield or selectivity (although this reaction now required 48
h; entry 5). Upon moving to 5 equiv of amine H2SO4 salt
relative to Cu, the hydroxylated product was obtained in 97%
yield (97 turnovers of Pt) and 8:1 selectivity for 1 over 1a
(entry 6). To our knowledge, this result represents the highest
combination of terminal selectivity and TON reported to date
for Shilov-type Pt catalysis.4 Importantly, control reactions
he development of methods for the selective functional-
3
Tization of strong primary (1°) C(sp )−H bonds in the
presence of weaker tertiary (3°) and secondary (2°) C(sp3)−H
bonds remains a major challenge in the burgeoning field of
transition-metal-catalyzed C−H functionalization.1−3 The Pt-
catalyzed oxidation of alkanes offers a promising approach to
tackle this challenge.4 In the 1970s, Shilov demonstrated that
aqueous solutions of PtII and PtIV salts effect the C−H
hydroxylation of alkanes.5 These transformations generally
afford selective functionalization of 1° C−H bonds over 2° C−
H bonds.4,6 However, despite the great promise of Shilov-type
Pt catalysis, these transformations have found minimal
applications in organic synthesis over the past 40 years.7 This
is due, in large part, to three key limitations: (1) the scope of
substrates remains extremely narrow (predominantly due to the
low water solubility of most organic molecules); (2) the
selectivity remains modest (1° vs 2° C(sp3)−H bond selectivity
generally ranges from 1.5:1 to 3:1); and (3) costly PtIV salts are
typically used as the terminal oxidant (rendering the reactions
impractical even on small scales).
We reasoned that all of these challenges could potentially be
addressed in the context of the Pt-catalyzed C(sp3)−H
oxidation of aliphatic amines. Aliphatic amines are a very
important class of compounds that serve as the core structures
of diverse organic materials, natural products, and bioactive
molecules.8 Most existing methods for the C(sp3)−H
functionalization of aliphatic amines involve either (1)
functionalization at the highly activated C−H site α-to
nitrogen9 or (2) the use of the amine nitrogen as part of a
Received: August 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b09099
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Journal of the American Chemical Society
Communication
The observed increase in selectivity with shorter chain length
correlates with a decreased rate of C−H functionalization at
sites that are proximal to the ammonium cation. For example,
the C−H hydroxylation of N-ethylpyrrolidine to form 2
proceeded in modest 25% yield under conditions analogous
to those used to obtain products 3−5. This is consistent with β-
C(sp3)−H bonds being significantly less reactive than more
remote C−H sites. In addition, competition between N-propyl-
and N-butylpyrrolidine afforded a 10:7:1:<1 ratio of products
4-OH:3-OH:4a-OH:3a-OH (Scheme 1). Again, the selectivity
Table 1. Optimization of Pt-Catalyzed C−H Hydroxylation
of Protonated Dipropylamine
K2PtCl4
loading
(mol%)
yield of
a
equiv of
amine
temp
(°C)
1 + 1a
a
entry
oxidant
(%)
1:1a
b
1
2
2
2
2
2
5
5
5
5
K2PtCl6
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
−
120
120
150
150
150
150
150
150
150
10
10
10
1
36
66
63
40
70
97
>10:1
>10:1
>10:1
>10:1
8:1
b
2
c
3
Scheme 1. Competition between N-Propyl- and N-
Butylpyrrolidine
c
4
b
5
1
c
6
1
8:1
c
e
7
1
nd
−
−
−
c
e
8
CuCl2
−
1
nd
cd
,
9
CuCl2
<1
a
1
Yield and ratio of products determined by H NMR. Reactions were
conducted in sealed vials under an atmosphere of ambient air. Yields
are calculated based on the oxidant (K2PtCl6 or CuCl2) as the limiting
b
c
d
e
reagent. 48 h. 30 h. No H2SO4 added. Products 1 and 1a were not
detected.
for 4-OH over 3-OH as well as for 4a-OH over 3a-OH is
consistent with higher reactivity of C−H sites that are more
remote from nitrogen. Overall, these results support our
hypothesis that quaternization of the amine deactivates the
C(sp3)−H sites proximal to nitrogen via an inductive electron-
withdrawing effect.
show that no product is formed in the absence of Cu or Pt
(entries 7 and 8). Furthermore, <1% of the C−H hydroxylation
product was observed under the standard conditions but in the
absence of added acid (entry 9). This is consistent with our
hypothesis that protonation of the amine is essential for this
transformation.
We next examined the Pt-catalyzed C−H hydroxylation of a
series of N-alkylpyrrolidine substrates to probe the impact of
chain length on selectivity (Table 2). In all cases, the major
Our standard conditions proved effective for the C−H
hydroxylation of a variety of other 2° and 3° aliphatic amine
substrates (Table 3). In all cases, the site selectivity was
1
determined by H NMR spectroscopic analysis of the crude
reaction mixtures (see Supporting Information for spectra).17
The amino alcohol products were then derivatized with PivCl
to facilitate isolation and characterization. Notably, the oxidant
is used as the limiting reagent in these transformations. As such,
yields greater than 100% reflect regeneration of the Cu oxidant
(presumably by ambient air).19
Table 2. Pt-Catalyzed C−H Functionalization of N-
Alkylpyrrolidines
All of the examples in Table 3 display modest to excellent
terminal selectivity.17 Notably, the derivatization and purifica-
tion sequence generally results in an upgrade of selectivity for
the terminal product. The terminal selectivity partially reflects
the inherent steric preference of Pt for the activation of 1° over
2° or 3° C−H bonds.4,6 However, selectivity is highest in the
formation of the products in entries 1, 4, 5, and 7−10, where
the competing 2° C(sp3)−H sites are β or α to the quaternized
nitrogen. Again, these results implicate significant inductive
deactivation by the ammonium cation. Nitrogen heterocycles
including pyrrolidine, piperidine, and morpholine are compat-
ible with the reaction conditions, and minimal C−H oxidation
of the ring (<5%) is observed in these systems. Although
terminal β-C(sp3)−H sites are electronically deactivated,
triethylamine does undergo high-yielding β-C−H oxygenation
under slightly modified reaction conditions (15 equiv of amine
relative to CuCl2 over 48 h; entry 7). Minimal oxidation of tert-
butyl groups is observed, even in the absence of competing
terminal sites for C−H oxidation (e.g., entries 11 and 12).
Similar observations have been made by Hartwig in Ir-catalyzed
alkane borylation2 and can be attributed to steric deactivation
of the tert-butyl C−H bonds.
a
Crude selectivity determined by 1H NMR spectroscopic analysis
b
prior to treatment with PivCl. Yield determined by 1H NMR
spectroscopic analysis prior to treatment with PivCl.
product derived from C−H hydroxylation at the terminal
position. As the terminal methyl group is moved closer to the
amine nitrogen, the terminal selectivity increases sequentially
from 2:1 in 5 to >20:1 in 2.17 In all cases, the site selectivity was
1
determined by H NMR spectroscopic analysis of the crude
reaction mixture (see Supporting Information for spectra). The
amino alcohol products were then derivatized with pivaloyl
chloride (PivCl) to facilitate product isolation and character-
ization. Using these conditions, the oxygenated amino ester
products 3−5 were isolated in high yields.18
We next compared this C−H hydroxylation reaction to Ir-
catalyzed C−H borylation, the current state-of-the-art method
for terminal-selective alkane C−H functionalization.2 Hartwig
B
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Journal of the American Chemical Society
Communication
preference for 19-OH over 18-OH, and a 3:1 ratio of 19-OH to
19a-OH (Scheme 2b). These results highlight the comple-
mentarity of the two methods. Notably, Pt catalysis has the
additional advantages of compatibility with ambient air and
moisture as well as applicability to 1°, 2°, and 3° amine
substrates.
Table 3. Substrate Scope of Pt-Catalyzed C−H
Hydroxylation of Secondary and Tertiary Amines
a
A final set of investigations focused on probing the
mechanism of this transformation. In particular, we noted
that C−H hydroxylation products are formed exclusively under
our reaction conditions, despite the presence of a high
concentration of chloride. In other studies of Shilov-type
alkane C−H oxidation, mixtures of C−H chlorination and C−
H hydroxylation products have been reported under related
conditions.5,6,20 When the Pt-catalyzed C−H oxidation of
1
dipropylamine was monitored by H NMR spectroscopy, we
observed rapid initial formation of an intermediate (A), which
then fully converted to the C−H hydroxylation product over 24
h (Figure 1). Intermediate A was identified as the terminal C−
a
General conditions: 1 mol% K2PtCl4, 1 equiv of CuCl2, 5 equiv of
amine, 5.5 equiv of H2SO4 (1.1 equiv relative to amine), 150 °C,
b
c
24−48 h. Entry 6: amine used as HCl salt, 10 mol% K2PtCl4. Entry
d
7: 15 equiv of amine, 16.5 equiv of H2SO4. Entry 8: 0.5 mol%
e
K2PtCl4, 15 equiv of amine, 16.5 equiv of H2SO4. Entries 9−11: 5 mol
f
% K2PtCl4. Entries 11 and 12: amine used as HCl salt, 10 mol%
g
K2PtCl4; Yields estimated by 1H NMR analysis of crude reaction
mixtures; <5% of C(sp3)−H hydroxylation or C(sp3)−H chlorination
Figure 1. Formation and decay of intermediate A in the Pt-catalyzed
C−H oxidation of dibutylamine.
products was observed.
H chlorination product, based on in situ characterization by 1H
NMR spectroscopy, as well as independent synthesis of this
compound. We also confirmed that an authentic sample of A
undergoes quantitative conversion to 1 over 24 h at 150 °C in
H2O, both in the presence and in the absence of the Pt catalyst.
This suggests that a significant quantity of the hydroxylated
product 1 is formed from A via a nucleophilic substitution
reaction.
has recently reported that the 3° amine substrate diethylbutyl-
amine undergoes Ir-catalyzed C−H borylation to afford the
terminal β-C(sp3)−H borylation product 18-BPin with 6:1
selectivity over the analogous terminal δ-C(sp3)−H borylation
product 19-BPin (Scheme 2a).12 In this system, none of the 2°
C(sp3)−H borylation product 19a-BPin was reported. In
contrast, the Pt-catalyzed hydroxylation of this same substrate
provides completely different site selectivity, affording a >20:1
The data in Figure 1 suggest the feasibility of selectively
accessing C(sp3)−H chlorination products, particularly with
substrates in which nucleophilic substitution with H2O is slow.
As proof-of-principle, we subjected substrates 20 and 24 to our
Pt-catalyzed C−H oxidation conditions for short reaction times
Scheme 2. Comparison of Selectivity of (a) Ir-Catalyzed C−
H Borylation versus (b) Pt-Catalyzed C−H Oxygenation of
Diethylbutylamine
1
(2 h). Analysis of the crude reaction mixtures by H NMR
spectroscopy showed exclusive formation of the C−H
chlorination products 21 and 25. While 21 and 25 proved
challenging to isolate due to their high volatility, work-up of
these reactions with KHCO3 resulted in the formation of the
corresponding oxazinones 23 and 26, which were isolated in
65% and 55% isolated yield, respectively (Scheme 3). In
addition, the treatment of 21 with phenyl isothiocyanate
afforded 22 in 73% yield.
In conclusion, this Communication describes a Pt-catalyzed
method for the terminal-selective C(sp3)−H oxidation of
protonated aliphatic amines using CuII as the terminal oxidant.
These reactions proceed with some of the highest TONs and
selectivities reported to date for Pt-catalyzed alkane oxidation.
C
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Journal of the American Chemical Society
Communication
Scheme 3. Pt-Catalyzed C(sp3)−H Chlorination and
Subsequent Functionalization of 20 and 24
(6) (a) Labinger, J. A.; Herring, A. M.; Lyon, D. K.; Luinstra, G. A.;
Bercaw, J. E.; et al. Organometallics 1993, 12, 895. (b) Labinger, J. A.;
Herring, A. M.; Bercaw, J. E. J. Am. Chem. Soc. 1990, 112, 5628.
(7) For synthetic applications, see: (a) Kao, L.-C.; Sen, A. J. Chem.
Soc., Chem. Commun. 1991, 1242. (b) Basickes, N.; Sen, A. Polyhedron
1995, 14, 197−202. (c) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am.
Chem. Soc. 2001, 123, 8149. (d) Lin, M.; Shen, C.; Garcia-Zayas, E. A.;
Sen, A. J. Am. Chem. Soc. 2001, 123, 1000. (e) Lee, J. M.; Chang, S.
Tetrahedron Lett. 2006, 47, 1375. (f) Weinberg, D. R.; Labinger, J. A.;
Bercaw, J. E. Organometallics 2007, 26, 167. (g) Chen, G. S.; Labinger,
J. A.; Bercaw, J. E. Organometallics 2009, 28, 4899.
(8) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
(9) For examples of the α-C−H oxygenation of amines, see: (a) Kim,
S.; Ginsbach, J. W.; Lee, J. Y.; Peterson, R. L.; Liu, J. J.; Siegler, M. A.;
Sarjeant, A. A.; Solomon, E. I.; Karlin, K. D. J. Am. Chem. Soc. 2015,
We propose that protonation of the amine is critical to the
success of these transformations for several reasons. First,
protonation renders the substrates water-soluble. Second,
protonation prevents deactivation of the catalyst/oxidant by
amine binding. Finally, the inductive electron-withdrawing
ammonium cation electronically deactivates proximal C−H
bonds, resulting in high selectivity for terminal C(sp3)−H sites
that are remote to nitrogen. Efforts to design second-generation
Pt catalysts that exhibit enhanced efficiencies and terminal
selectivities in this transformation are underway in our
laboratory and will be reported in due course.
́
137, 2867. (b) Genovino, J.; Lutz, S.; Sames, D.; Toure, B. B. J. Am.
̈
Chem. Soc. 2013, 135, 12346. (c) Ling, Z.; Yun, L.; Liu, L.; Fu, X.; Wu,
B. Chem. Commun. 2013, 49, 4214. (d) Liu, P.; Liu, Y.; Wong, E. L.-
M.; Xiang, S.; Che, C.-M. Chem. Sci. 2011, 2, 2187. (e) Park, J.;
Morimoto, Y.; Lee, Y.-M.; You, Y.; Nam, W.; Fukuzumi, S. Inorg.
Chem. 2011, 50, 11612. (f) Murahashi, S.; Naota, T.; Yonemura, K. J.
Am. Chem. Soc. 1988, 110, 8256.
(10) (a) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J.
Nature 2014, 510, 129. (b) Smalley, A. P.; Gaunt, M. J. J. Am. Chem.
Soc. 2015, 137, 10632.
(11) For examples of protected amines as directing groups for
C(sp3)−H oxidation, see: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis,
O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Zhang, S.; He, G.; Zhao, Y.;
Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313.
(c) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu,
J. Q. Nat. Chem. 2014, 6, 146.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b09099.
■
S
(12) For a complementary strategy involving terminal-selective, Ir-
catalyzed C−H borylation of aliphatic amines, see: Li, Q.; Liskey, C.
W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 8755.
Experimental and spectral details for all new compounds
and all reactions reported as well full details on selectivity
determination from crude reactions (PDF)
(13) Isaacs, N. S. Physical Organic Chemistry. 2nd ed.; Longman
Group Limited: London, 1995; p 146−192.
(14) Inductive electron-withdrawing groups are known to deactivate
adjacent C−H bonds toward Pt-catalyzed C(sp3)−H activation. For
example, see ref 7d and the following: Periana, R. A.; Taube, D. J.;
Gamble, S.; Taube, H.; Satoh, T.; Fujii, H. Science 1998, 280, 560.
(15) For a later example of CuCl2 as an oxidant in Shilov chemistry,
see ref 7e and the following: Wang, Z.; Sugiarti, S.; Morales, C. M.;
Jensen, C. M.; Morales-Morales, D. M. Inorg. Chim. Acta 2006, 359,
1923.
AUTHOR INFORMATION
Corresponding Author
*mssanfor@umich.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(16) (a) Maeda, Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn.
2003, 76, 2399. (b) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.;
Kozlowski, M. C. Chem. Rev. 2013, 113, 6234.
■
We acknowledge funding from NIH, NIGMS (GM073836).
M.L. thanks the NSF for a graduate fellowship. We also
acknowledge Dr. Sarah J. Ryan for helpful discussions.
(17) The only internal chain oxidation products detected in more
than trace quantities were at the site that is one carbon away from the
terminal position. Additionally, only small amounts of products
derived from C−H functionalization on the pyrrolidine ring were
observed, except with N-ethylpyrrolidine. In the latter case, we
estimate that ∼15% of ring oxidation products are formed.
(18) The yields are based on CuCl2·2H2O as the limiting reagent.
Since Cu is a 1e− oxidant, 100% yield = 0.5 × mmol CuCl2·2H2O
added to the reaction. Yields above 100% reflect regeneration of Cu by
ambient air.
(19) The NMR yield of the C−H hydroxylation to form 4 under our
standard conditions was 142%. When this same reaction was
conducted under an atmosphere of N2 (rather than air), a significantly
lower yield of 41% was obtained. Furthermore, when the reaction
under air was conducted in a small vessel (4 mL vs 10 mL sealed vial),
the yield decreased to 47%. All of these pieces of data are consistent
with the proposal that the O2 (in air) is turning over the Cu.
(20) (a) Luinstra, G. A.; Wang, L.; Stahl, S. S.; Labinger, J. A.;
Bercaw, J. E. J. Organomet. Chem. 1995, 504, 75. (b) DeVries, N.; Roe,
D. C.; Thorn, D. L. J. Mol. Catal. A: Chem. 2002, 189, 17.
REFERENCES
■
(1) (a) Crabtree, R. H. Chem. Rev. 1985, 85, 245. (b) Shilov, A. E.;
Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. (c) Crabtree, R. H. J. Chem.
Soc., Dalton Trans. 2001, 2437. (d) Labinger, J. A.; Bercaw, J. E. Nature
2002, 417, 507. (e) Per
́
ez, P. J. Alkane C-H Activation by Single-Site
Metal Catalysis; Perez, P. J., Ed.; Catalysis by Metal Complexes, Vol.
́
38; Springer: Dordrecht, The Netherlands, 2012.
(2) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992.
(3) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010,
110, 704. (c) Nam, W. Acc. Chem. Res. 2007, 40, 522. (d) White, M. C.
Science 2012, 335, 807.
(4) (a) Lersch, M.; Tilset, M. Chem. Rev. 2005, 105, 2471. (b) Stahl,
S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37,
2180. (c) Shilov, A. E.; Shteinman, A. A. Coord. Chem. Rev. 1977, 24,
97.
(5) (a) Gol’dshlger, N. F.; Tyabin, M. B.; Shilov, A. E.; Shteinman, A.
A. Zh. Fiz. Khim. 1969, 43, 2174. (b) Gol’dshlger, N. F.; Eskova, V. V.;
Shilov, A. E.; Shteinman, A. A. Zh. Fiz. Khim. 1972, 46, 1353.
D
DOI: 10.1021/jacs.5b09099
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