Supramolecular recognition allows remote, site-selective C-H oxidation of methylenic sites in linear amines

Article abstract of DOI:10.1002/anie.201709280

Site-selective C-H functionalization of aliphatic alkyl chains is a longstanding challenge in oxidation catalysis, given the comparable relative reactivity of the different methylenes. A supramolecular, bioinspired approach is described to address this challenge. A Mn complex able to catalyze C(sp³)-H hydroxylation with H₂O₂ is equipped with 18-benzocrown-6 ether receptors that bind ammonium substrates via hydrogen bonding. Reversible pre-association of protonated primary aliphatic amines with the crown ether selectively exposes remote positions (C8 and C9) to the oxidizing unit, resulting in a site-selective oxidation. Remarkably, such control of selectivity retains its efficiency for a whole series of linear amines, overriding the intrinsic reactivity of C- H bonds, no matter the chain length.

Full text of DOI:10.1002/anie.201709280

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Accepted Article
Title: Supramolecular recognition allows remote, site-selective C-H
oxidation of methylenic sites in linear amines
Authors: Giorgio Olivo, Giulio Farinelli, Alessia Barbieri, Osvaldo
Lanzalunga, Stefano Di Stefano, and Miquel Costas
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10.1002/anie.201709280
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Supramolecular recognition allows remote, site-selective C-H
oxidation of methylenic sites in linear amines
Giorgio Olivo,[a]* Giulio Farinelli,[b] Alessia Barbieri,[b]Osvaldo Lanzalunga,[b] Stefano Di Stefano[b]* and
Miquel Costas[a]*
Abstract: Site-selective C-H functionalization of aliphatic alkyl chains
stands as a longstanding challenge in oxidation catalysis, given the
comparable relative reactivity of the different methylenes. Herein, we
describe a supramolecular, bioinspired approach to address this
challenge. We designed a Mn complex, able to catalyze C(sp3)-H
hydroxylation with H2O2, equipped with 18-benzocrown-6 ether
receptors that bind ammonium substrates via hydrogen bonding.
Reversible pre-association of protonated primary aliphatic amines
with the crown ether selectively exposes remote positions (C8 and
C9) to the oxidizing unit, resulting in a site-selective oxidation.
Remarkably, such control of selectivity retains its efficiency for a
whole series of linear amines, overriding the intrinsic reactivity of C-H
bonds, no matter the chain length.
approach, although the strict shape and size complementarity
required for recognition limited the scope to few, well-crafted
substrates (Figure 1).
Nevertheless, we reasoned that this approach may permit
the elusive remote oxidation of alkyl chains.1b,3b,6,11 Towards this
aim, we designed catalysts 1-Mn and 1-Fe (Scheme 2, synthesis
and characterization in the SI, pages 16-38) equipped with 18-
benzocrown-6 ether (BC) receptors to bind and orient primary
ammonium ions15 (Figure 1). The catalytic center is a Mn12 or Fe13
PDP complex (2-M, Scheme 2), known to catalyze aliphatic C-H
hydroxylation with H2O2 and acetic acid (AcOH).14 Simple
protonation of linear alkyl amines would provide optimal
substrates to test our hypothesis.16
As anticipated, titration of 1-Fe with protonated decylamine
3 results in a strong 1:2 binding (both Kass≥104 M-1, pages 39-43
in SI) in CD3CN at -40°C. At this temperature the complex, that is
Unfolding the great potential of C-H oxidations in synthesis
requires a precise and predictable control over reaction site-
selectivity. Nature masters this control by precisely orienting the
substrates towards the enzyme active site by means of multiple
weak interactions. Conversely, artificial catalysts struggle to
achieve such selectivity.1 The problems faced are well highlighted
in the selective hydroxylation of alkyl chains, a longstanding
challenge in oxidation catalysis. The strength of their C-H bonds
(~96 kcal mol-1) coupled with the lack of appreciable differences
in electronic and steric properties makes the internal methylenes
practically indistinguishable (Scheme 1).1 As a consequence,
oxidation of alkyl chains affords statistical mixtures of products,
only slightly affected by the use of very bulky catalysts.2 A good
selectivity can be only attained via intramolecular reactions, using
a directing group1a,3,4 or incorporating the reactant into the
substrate5 (Scheme 1). However, this strategy has two limitations:
it cannot access C-H bonds outside a short range (β, γ or δ
positions) and requires stoichiometric, preinstalled directing (or
reactive) groups.6
Supramolecular chemistry may offer a way past these
limitations.8,9 Reversible binding of the substrate to a receptor
anchored to the catalyst can expose specific C-H bonds to the
oxidizing unit, thus determining the selectivity of the hydroxylation
(Scheme 1). Seminal works10 demonstrated the feasibility of this
Scheme 1. Different approaches to the selective oxidation of alkyl chains.
[a]
[b]
Dr. G. Olivo, Dr. M. Costas
Institut de Química Computacional i Catàlisi (IQCC) and
Departament de Química
Universitat de Girona
Campus de Montilivi, 17071 Girona, Spain
E-mail: giorgio.olivo@udg.edu, miquel.costas@udg.edu,
G. Farinelli, A. Barbieri, Dr. O. Lanzalunga, Dr. S. Di Stefano
Dipartimento di Chimica and Istituto CNR di Metodologie Chimiche
(IMC-CNR), Sezione Meccanismi di Reazione
Sapienza Università di Roma
P.le A. Moro 5, I-00185 Rome, Italy
E-mail: stefano.distefano@uniroma1.it
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Catalysts used in this work.
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Figure 1. Supramolecularly directed C-H oxidations.
paramagnetic at 25°C, turns diamagnetic due to a temperature
dependent spin crossover, enabling H-NMR spectroscopy (see
observed. A similar, but lower, effect was also found for Fe-based
complexes (entries 3 and 4).
1
SI pages 21-22). The paramagnetism of 1-Mn does not allow
NMR titration, but mass spectrometry reveals analogous 3
binding (see SI page 44). Remarkably, the recognition tolerates
the competitive hydrogen bond partners (AcOH and H2O)
required for H2O2 activation,14 and is specific for primary
ammonium ions (see SI pages 45-50).15
A series of control experiments were carried out to assess
whether the observed change in selectivity were really due to
supramolecular recognition. i) Addition of free BC does not modify
the selectivity of the parent 2-Mn complex, indicating that
substrate binding to BC does not affect its reactivity (entries 5-7).
Increasing BC loadings reduce conversion, probably because of
competitive ether oxidation. ii) The selectivity amplification does
not derive from increased steric hindrance, since the bulky
catalyst TIPS2-Mn18 affords the same selectivity pattern of 2-Mn
(entry 8). iii) Saturation of the receptor by prior coordination of
Ba(ClO4)2 fully suppresses the selectivity amplification of 1-Mn
(entry 9). iv) Replacement of NH bonds in 3 with N-methyl ones
The electronic properties of 1-Fe are hardly affected by the
build-up of positive charge due to cation binding. Neither the
FeIII/FeII redox potential nor the energy of the MLCT Vis band nor
the catalytic hydroxylation of 1-Fe and 1-Mn are significantly
+
altered upon coordination of NH4 , K+, Ca2+ or Ba2+ cations (see
SI pages 78-81, 86). The only notable changes are related to the
BC moiety, which becomes harder to oxidize both chemically and
electrochemically (see SI pages 78, 85).
+
(DecNH2Me+, DecNHMe2 ) undermines the affinity of the
substrate for the crown ether and yields the same selectivity
pattern, no matter the catalyst used (entries 10-14). However,
when there are no cationic guests that shield the BC moiety from
oxidation (see SI page 85), low product yields are obtained with
At this point, we selected decylammonium 3 as a model
substrate to test our approach. Non-directed oxidation with 2-Mn
yields a mixture of ketone products (K3-K9, ketones at C3-C9,
Table 1, entry 1). The first positions (up to C5) are shielded by the
nearby ammonium positive charge,16 the last positions are slightly
activated due to improved sterical accessibility (C8 and C9, 53%
of the total yield), and a statistical oxidation occurrs in the middle
of the chain (C6, C7). To our delight, catalyst 1-Mn substantially
modified this selectivity, enhancing the selectivity for C8 and C9
positions up to 81% (entry 2).17 A concomitant decrease (C5-C7)
or suppression (C3, C4) of the oxidation on the other sites is
+
1-Mn. Consistently, addition of readily exchangeable NH4
(3mol%) increases the yield (entry 14). v) Competitive oxidation
of 3 and a neutral, more reactive substrate with methylene units
(4) or weak tertiary C-H bonds (5) results in preferential
hydrocarbon oxidation with 2-Mn (Scheme 3). 1-Mn induces a full
reversal of this selectivity, which is lost upon addition of Ba2+
(Scheme 3). All these experiments consistently point to a
recognition-driven selectivity, which overrides the intrinsic
reactivity of the substrate C-H bonds.
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Table 1: 3 oxidation mediated by different catalysts.a
Conv/
C8 + C9
Selecti-
vityb
Substrate
Additive
mol%
Entry
cat
tot yield
(%)
(BF4- anion)
K3
K4
K5
K6
K7
K8
K9
1
2
3
4
5
6
7
2-Mn
1-Mn
2-Fe
1-Fe
2-Mn
2-Mn
2-Mn
DecNH3+(3)
43/34
50/36
48/36
36/30
41/35
25/21
8/traces
0.5%
2%
2.5%
5.5%
5.5%
8%
10%
16%
10%
12%
10%
6%
53%
81%
45%
61%
51%
54%
“
“
“
“
“
“
“
-
-
0.5%
-
0.5%
4%
1.5%
8%
5%
6%
3%
-
5%
8%
6%
6%
3%
-
13%
7%
6%
7.5%
5%
-
-
-
0.5%
3%
BC 2%
0.5%
0.5%
-
1.5%
1%
-
1.5%
-
BC 10%
-
BC 100%
TIPS2-
8
62/34
traces
1%
2%
5%
8%
8%
10%
53%
Mn
9
1-Mn
1-Mn
2-Mn
1-Mn
2-Mn
1-Mn
“
Ba2+ 3%c
47/27
9/7
traces
traces
0.5%
traces
-
2%
0.5%
1%
2%
0.5%
3%
5%
5%
6%
2%
8%
2%
58%
50%
49%
50%
52%
50%
+
10
DecNMeH2
1.5%
4.5%
0.5%
7.5%
1%
1.5%
4.5%
0.5%
7.5%
1%
11
“
28/26
11/3
60/47
12/6
5%
7.5%
0.5%
14%
2%
12d
13d
14d
DecNMe2H+
traces
2.5%
0.5%
traces
5%
0.5%
10%
1%
“
“
NH4+ 3%e
traces
0.5%
aReaction conditions: cat 1 mol% (3 mol% for Fe cat.), substrate 1 eq (95 mM, 0.38 mmol), H2O2 2.5 eq (15 min. addition by syringe pump), AcOH 22
eq (7 eq fot Fe cat.), CH3CN, 0°C. After 30 min., internal standard (biphenyl), Et3N, Ac2O and CH2Cl2 were added. After 1 hour, the mixture was washed
with H2O, H2SO4 1M, sat. NaHCO3, H2O, dried and analysed by GC. All reactions have been carried out in triplicate. Error ± 0.5%. Traces of acetylated
alcohols were detected, with a selectivity pattern superimposable to that of the main ketone products. bDefined as (K8+K9)/tot. yield). cBa(ClO4)2.
dDifferent workup, see SI page 80. eNH4PF6.
Scheme 3: Competition experiments.
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Then, we investigated the oxidation of a series of protonated, long-chain amines, while oxidation on positions before C8 and
linear amines, whose chain length spans from C6 to C14, aiming
after C10 fade away. Such bell-shaped profile is again consistent
with a supramolecular site-selectivity, with the receptor placing
mainly C8 and C9 C-H bonds in the reach of the oxidizing species.
To sum up, we designed a supramolecular catalyst that
oxidizes linear amines with a predictable site selectivity for C8 and
C9 positions. To the best of our knowledge, this is the first report
of a selective, remote C-H functionalization of alkyl chains. The
at determining the precise oxidation site of 1-Mn (Scheme 4). No
+
oxidation occurs with short amines (C6-NH3 ), likely due to the
strong deactivation exerted by the proximal positive charge. As
the chain length increases, ketone products are formed. Catalyst
2-Mn (Figure 2A) affords an almost statistical distribution of
ketone products, except for C3-C5 (electronically deactivated)
and the last two methylene units (sterically activated). Conversely, key for such selectivity lies in a substrate recognition that brings
the distribution obtained with 1-Mn (Figure 2B) reveals a bell-
shaped profile, with the maximum yields on C8 and C9 sites, no
matter the chain length. K10 becomes a secondary product in
these C-H bonds in the range of the active unit. Remarkably, this
control of selectivity is not affected by the chain length or the
presence of more (sterically) activated positions.
Figure 2: Distribution of oxidation products in 2-Mn (A) and 1-Mn (B) catalyzed
oxidation of linear amines.
Scheme 4.
Scientifica –Anno 2014). The authors thank Mr. Giorgio Capocasa
for technical assistance.
Acknowledgements
MC acknowledge MINECO of Spain (CTQ2015-70795-P), the
Catalan DIUE (2009SGR637, ICREA Academia award) and STR
of UdG for experimental support. S.D.S acknowledges MIUR,
PRIN 2010CX2TLM and Sapienza Università di Roma (Ricerca
Keywords: Bioinspired catalysis • Supramolecular chemistry •
C-H oxidation • Regioselectivity • Molecular recognition
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[1]
a) T. Brück, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem. Res. 2012,
45, 826-839; b) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281-
292; c) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011, 50,
3362-3374.
Thordarson, E. J. A. Bijsterveld, A. E. Rowan, R. J. M. Nolte, Nature 2003,
424, 915-918; d) T. Šmejkal,B. Breit, Angew. Chem. Int. Ed. 2008, 47,
311-315. e) P. Dydio, W. I. Dzik, M. Lutz, B. de Bruin, J. H. Reek, Angew.
Chem. Int. Ed. 2011, 50, 396-400. f) S. Korom, P. Ballester, J. Am. Chem.
Soc. 2017, 139, 12109-12112.
[2]
[3]
a) M J. Nappa, C. A. Tolman, Inorg. Chem. 1985, 24, 4711-4719; b) B.
R. Cook, T. J. Reinert, K. S. Suslick, J. Am. Chem. Soc. 1986, 108, 7281-
7286.
[10] a) Breslow, R.; Huang, Y.; Zhang, X.; Yang, J., Proc. Nat. Ac. Sci. USA
1997, 94, 11156-11158; b) Breslow, R.; Zhang, X.; Huang, Y., J. Am.
Chem. Soc. 1997, 119, 4535-4536. c) S. Das, C. D. Incarvito, R. H.
Crabtree, G. W. Brudvig, Science 2006, 312, 1941-1943. d) J. R. Frost,
S. M. Huber, S. Breitenlechner, C. Bannwarth, T. Bach, Angew. Chem.
Int. Ed. 2015, 54, 691-695.
a) B. Li, M. Driess, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 6586-
6589; b) M. A. Bigi, S. A. Reed, M. C. White, J. Am. Chem. Soc. 2012,
134, 9721-9726.
[4]
[5]
[6]
K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 7247-
7249.
[11] a) M. S. Chen, M. C. White, Science 2010, 327, 566-571; b) G. Asensio,
M. E. Gonzalez-Nunez, C. B. Bernardini, R. Mello, W. Adam, J. Am.
Chem. Soc. 1993, 115, 7250-7253.
a) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272-275; b) G. J. Choi, Q.
Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268-271.
a) R. Breslow, M. A. Winnik, J. Am. Chem. Soc. 1969, 91, 3083-3084; b)
R. Breslow, J. Rothbard, F. Herman, M. L. Rodriguez, J. Am. Chem. Soc.
1978, 100, 1213-1218.
[12] R. V. Ottenbacher, D. G. Samsonenko, E. P. Talsi, K. P. Bryliakov,
Org.Lett. 2012, 14, 4310-4313.
[13] M. S. Chen, M. C. White, Science 2007, 318, 783-787.
[14] a) W. N. Oloo, L. Que, Jr., Acc. Chem. Res. 2015, 48, 2612-2621; b) G.
Olivo, O. Cussó, M. Costas, Chem. – As. J. 2016, 11, 3148-3158.
[15] R. M. Izatt, K. Pawlak, J. S. Bradshaw, R. L. Bruening, Chem. Rev. 1991,
91, 1721-2085.
[7]
a) D. H. Sherman, S. Li, L. V. Yermalitskaya, Y. Kim, J. A. Smith, M. R.
Waterman, L. M. Podust, J. Biol. Chem. 2006, 281, 26289-26297; b) S.
Negretti, A. R. H. Narayan, K. C. Chiou, P. M. Kells, J. L. Stachowski, D.
A. Hansen, L. M. Podust, J. Montgomery, D. H. Sherman, J. Am. Chem.
Soc. 2014, 136, 4901-4904.
[16] a) M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2015, 137, 12796-12799;
b) J. M. Howell, K. Feng, J. R. Clark, L. J. Trzepkowski, M. C. White, J.
Am. Chem. Soc. 2015, 137, 14590-14593.
[8]
[9]
a) P. Dydio, J. N. H. Reek, Chem. Sci. 2014, 5, 2135-2145; b) H. J. Davis,
R. J. Phipps, Chem. Sci. 2017, 8, 864-877.
Selected examples of recognition-driven C-H borylation: a) Y. Kuninobu;
H. Ida; M. Nishi; M. Kanai, Nat. Chem. 2015, 7, 712-717; d) H. J. Davis;
M. T. Mihai; R. J. Phipps, J. Am. Chem. Soc. 2016, 138, 12759-12762.
Selected examples of recognition-driven olefin functionalization: c) P.
[17] 1-Mn does not distinguish between C8 and C9, probably for a residual
flexibility of the substrate-catalyst adduct.
[18] M. Milan, M. Bietti, M. Costas, ACS Cent. Sci. 2017, 3, 196-204.
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Entry for the Table of Contents (Please choose one layout)
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Supramolecular C-H oxidation:
Supramolecular recognition of
Giorgio Olivo,* Giulio Farinelli, Alessia
Barbieri, Osvaldo Lanzalunga, Stefano
Di Stefano* and Miquel Costas*
protonated primary amines on 18-
crown-6 receptors exposes specific,
remote methylenes to the Mn active
site. Linear alkyl chains can thus be
selectively oxidized on C8 and C9
positions with H2O2, overriding the
intrinsic reactivity of C-H bonds.
Page No. – Page No.
Supramolecular recognition allows
remote, site-selective C-H oxidation
of methylenic sites in linear amines
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