A deep cavitand receptor functionalized with Fe(II) and Mn(II) Aminopyridine complexes for bioinspired oxidation catalysis

Article abstract of DOI:10.1021/acscatal.7b04426

A deep cavitand receptor 2 based on a resorcinarene scaffold and functionalized with a bis(pyridyl)dipyrrolidine tetradentate ligand has been obtained. Binding of divalent metal ions (M²⁺ = Mn²⁺, Fe²⁺, and Zn²⁺)

Full text of DOI:10.1021/acscatal.7b04426

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A Deep Cavitand Receptor Functionalized with Fe(II) and Mn(II)
Aminopyridine Complexes for Bioinspired Oxidation Catalysis.
Diego Vidal, Miquel Costas, and Agustí Lledó
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b04426 • Publication Date (Web): 21 Mar 2018
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A Deep Cavitand Receptor Functionalized with
Fe(II) and Mn(II) Aminopyridine Complexes for
Bioinspired Oxidation Catalysis.
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Diego Vidal, Miquel Costas,* and Agustí Lledó*
Institute of Computational Chemistry and Catalysis, and Department of Chemistry, Universitat
de Girona, c/Maria Aurèlia de Capmany 69, 17003 Girona, Spain.
ABSTRACT: A deep cavitand receptor 2 based on a resorcinarene scaffold and functionalized
with a bis(pyridyl)dipyrrolidine tetradentate ligand has been obtained. Binding of divalent metal
2+
2+
2+
2+
ions (M = Mn , Fe and Zn ) at the tetradentate ligand results in the formation of cavitand
complexes 2·M(OTf) . The complexes exhibit selective binding of alkylammonium ions and
2
amides within the cavitand. 2·M(OTf) (M = Fe(II) and Mn(II)) catalyze selective hydroxylation
2
of aliphatic C–H bonds and epoxidation of olefins with hydrogen peroxide, exhibiting selectivity
patterns consistent with the implication of high valent metalꢀoxo species. Furthermore,
ꢀ
2+
2·Fe(OTf) reacts with IO to form an oxoiron(IV) complex [2·Fe(O)] , without decomposition
2
4
of the supramolecular container. This species is relatively stable at 0 °C, yet engages in fast
oxygen atom transfer reactions.
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KEYWORDS: supramolecular chemistry, cavitands, bioinspired catalysis, oxidation catalysis,
nonꢀheme metal complexes, high valent oxo species.
INTRODUCTION
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The mimicry of enzymatic catalysis with artificial systems has been a long standing goal of
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synthetic supramolecular chemistry. It is now widely accepted that, in order to rival the
proficiency of enzymes, an artificial system must be built so that it defines a confined space
where the substrate is isolated from bulk medium and exposed to direct contact with appropriate
functional groups, a distinct feature of proteins and enzymes. The large and diverse family of
metalꢀdependent oxidation enzymes provides remarkable examples of such specialized
microenvironments, in which highly reactive transition metal centers are contained and kept
from reacting with the protein backbone, while effecting selective oxidations of complementary
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substrates.
Significant advances in the mimicry of enzymatic oxidations have been made employing
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carefully designed synthetic coordination compounds of assorted transition metals. Among
these, nonꢀheme Fe and Mn complexes bearing tetradentate nitrogen chelating ligands stand out
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because of their oxidation prowess. Such complexes are appealing from the synthetic point of
view: they are efficient oxidants of C–H and C=C bonds –even at low catalyst loadings–
employing green oxidants such as hydrogen peroxide, they can perform asymmetric reactions,
and they are based on abundant first row transition metals. Overall, these catalysts represent a
green and sustainable option for oxidative transformations of organic compounds. However, the
incorporation of the aforementioned Fe and Mn coordination manifolds into a supramolecular
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scaffold with a confined space suitable for substrate binding remains virtually unexplored. This
approximation has the potential to unveil new reactivity patterns, and even to override the innate
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selectivity of a substrate when multiple C–H or C=C bonds are present. We present herein our
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first take on this approach, combining a selfꢀfolding deep cavitand receptor with a
bis(pyridyl)dipyrrolidine (pdp) chelator suitable for Fe and Mn catalyzed oxidation chemistry
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(Fig. 1).
RESULTS AND DISCUSSION
Resorcinareneꢀbased selfꢀfolding cavitands (1, Fig. 1) are capable of binding small
hydrophobic molecules and organic cations whose exchange process is regulated by a seam of
hydrogen bonded secondary amides akin to that defining secondary structure in proteins. More
importantly, desymmetrized versions are accessible which allow the incorporation of inwardly
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directed functional groups, allowing the stabilization of elusive reactive intermediates and
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enabling biomimetic organocatalysis. Several metal containing receptors have also been
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,10,11
prepared with this approach.
For our receptor 2 (Fig. 1), we decided to use an acetal bridge
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as the attaching point for the ligand –rather than the more customary benzimidazole moiety–
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,10aꢀe
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with the aim of bringing the metal reactive center as close as possible to the deep section
of the cavity. Preliminary modelling studies suggested that a meta substituted pyridine would
provide a relatively unhindered metal coordination site on the side of the cavity. Bearing in mind
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the importance of ligand effects on Fe/Mn oxidation chemistry, we sought to develop a
synthetic plan amenable to modification and diversification at a late stage. Unlike other ironꢀ
containing supramolecular constructs, our design combines a sizable molecular recognition motif
1
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with a structured and wellꢀdefined coordination environment.
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Figure 1. The parent octa(amido) selfꢀfolding cavitand 1 and its bis(pyridyl)dipyrrolidineꢀ
functionalized derivative 2 (some fragments omitted for clarity).
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The synthesis of 2 started from the versatile hexaamidoꢀdiol cavitand 3 (Scheme 1). After
some experimentation, we found that condensation of 3 with meta substituted dibromomethyl
1
5
pyridine 4 proceeded cleanly and in good yield. Pyridine building block 4 was prepared in 3
steps from commercially available 2ꢀbromoꢀ5ꢀmethylpyridine (see SI). Mesylation of hydroxyl
derivative 5 with mesyl chloride proceeded with concomitant substitution by chloride to deliver
key intermediate 6, which was univocally characterized by Xꢀray crystallography. Nucleophilic
displacement of 2ꢀcloromethylpyridine derivative 6 with secondary amines appears as an
attractive entry into structurally diverse cavitandꢀligand hybrids. For the work presented herein
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we chose to use known pyridyl bispyrrolidine (S,S)ꢀ7a, which reacted smoothly with 6 in the
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presence of base to deliver cavitand 2 in good yield. Cavitand 2 was characterized by H and C
NMR, HRMS and EA (see SI).
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Scheme 1. Synthesis of cavitand 2 (only one of the interconverting cyclodiastereomers is
depicted).
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The directionality established on of the hydrogen bond seam formed by the amide groups
renders cavitand 1 chiral. In the absence of hydrogen bond disrupting molecules, 1 exists as an
even mixture of two cycloenantiomers which interconvert slowly relative to the NMR time
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scale. Accordingly, 2 must exist –by virtue of the added homochiral ligand fraction– as an
undetermined mixture of cyclodiastereomers. These may appear as different sets of signals in the
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H NMR spectrum, complicating further analysis. However, in the presence of acetoneꢀd amide
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rotation is fast in the NMR time scale, notably simplifying the H NMR spectrum (Fig. 2).
Because of its distance to the chiral backbone of the ligand, the amide NH’s experience little
magnetic asymmetry, and therefore appear as three separate resonances only.
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Figure 2. Selected regions and assignment of the H NMR spectrum of 2 (400 MHz, acetoneꢀd ).
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With cavitand 2 in hand, we then proceeded to explore its coordination chemistry with
different transition metals (Scheme 2). Upon reaction with Fe(II), Mn(II) or Zn(II) triflate salts in
THF, the corresponding cavitand complexes were obtained cleanly as crystalline materials. The
formation of the corresponding Fe and Mn complexes can be followed by UVꢀVis spectroscopy,
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and in the case of the Zn complex by HꢀNMR spectroscopy. For the three cases, titration
experiments confirm that each cavitand only binds one metallic center (see the SI). Interestingly,
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the Fe complex displays only subtle paramagnetic effects in its H NMR spectra at 300K,
indicating that the ferrous center is in the diamagnetic low spin state. This is in sharp contrast to
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the parent [Fe(pdp)(CH CN) ] family of complexes, that possess high spin ferrous centers,
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suggesting a subtle influence of the cavitand in modulating the electronic properties of the metal
center. We also prepared the analogous Zn complex as a surrogate devoid of paramagnetic
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interferences, in order to better study the hostꢀguest properties of our system by H NMR. In
addition to triflate ligated compounds with potential for catalysis (vide infra), we obtained an Fe
dimer coordinated analogue by treatment of 2 with FeCl and subsequent exposure to air.
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Crystals of 2·Fe Cl O suitable for Xꢀray diffraction were obtained, which revealed the desired
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coordination arrangement through the tetradentate ligand facing the cavity of the receptor
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(
Scheme 2). Importantly, this layout does not interfere with binding of small molecules in the
cavity (occupied by solvent in the structure obtained).
Scheme 2. Complex synthesis and Xꢀray diffraction structure of 2·Fe Cl O (gray: C, blue: N,
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red: O, green: Cl, orange: Fe; solvent molecules omitted for clarity).
Next, we proceeded to evaluate the hostꢀguest properties of cavitand 2 and its metal
complexes. We chose to use acetonitrile as a solvent preferentially, since it is the most suitable
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for Feꢀ or Mnꢀ catalyzed oxidations. Resorcinareneꢀbased deep cavitands typically abhor polar
solvents such as methanol or acetonitrile, forcing the adoption of a flat kite conformation which
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dimerizes through πꢀπ stacking interactions. In our case, however, the methine resonances at
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conformation in each case (see the SI). The addition of the nitrogenated ligand or its cationic
complexes renders the cavity less hydrophobic and allows the accommodation of more polar
guests, as seen in the Xꢀray structures obtained. Neutral guests with wellꢀestablished
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complementarity for 1, such as 1ꢀadamantanecarbonitrile (8a, Fig. 3), do not displace the
solvent molecules in the cavity to provide kinetically stable complexes with 2·M(OTf) . The
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addition of a cationic anchor enables the formation of kinetically stable complexes, diagnosed by
the occurrence of resonances in the far upfield region of the spectrum (
δ 0 to ꢀ4 ppm),
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corresponding to buried aliphatic protons (Figure 3). The large upfield shifts observed are
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consistent with the receptor retaining the vase conformation, and the chemical shifts of the
methine protons in the resulting hostꢀguest complexes corroborate this hypothesis (see SI).
Guests 8bꢀc, 9 and 10 bind with their bulky aliphatic portions buried deep in the aromatic cavity
through CHꢀπ interactions, leaving the ammonium group within suitable range to establish
additional interactions with the amide groups. For primary and secondary ammonium moieties
hydrogen bonding to the amide’s carbonyls is established, whereas quaternary ammonium
groups establish cationꢀdipole interactions when the charged portion is positioned near the rim,
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as is the case with 9. In the absence of such secondary interactions, a guests cannot compete
with the solvent which is present in large excess. Interestingly, ambidextrous guest 8c binds with
the smaller cyclohexyl moiety positioned in the cavity as ascertained by 2D NMR (see SI),
suggesting a slightly reduced binding space in the metalloꢀcavitands with respect to 1. Finally,
cyclohexylamine amides (11) are also good guests, thanks to the occurrence of hydrogen
bonding interactions with the other amide groups on the rim of the cavity.
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Figure 3. Guests used in this study and upfield regions in the H NMR spectra of complexes
with 2·M(OTf) . a) In acetoneꢀd . b) in CD CN. c) at 298 K. d) at 240 K.
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We then proceeded to evaluate complexes 2·Fe(OTf) in representative iron catalyzed C–H
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and C=C bond oxidations using hydrogen peroxide as terminal oxidant (Scheme 3). Most
notably, 2·Fe(OTf) presents sustained catalytic activity in C–H hydroxylation and olefin
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epoxidation reactions. Monitoring of the iron species by ESIꢀMS during catalysis reveals that the
integrity of the complex is retained during the time course of the reaction. Under nonꢀoptimized
reaction conditions, hydroxylation of cisꢀ1,2ꢀdimethylcyclohexane and cisꢀdecalin occurs
selectively at the tertiary C–H bond, is stereospecific and the corresponding tertiary alcohol is
obtained in 34ꢀ35% yield. Minor amounts of products (3ꢀ9%) resulting from methylene
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oxidation are also obtained. Catalytic epoxidation of cisꢀβꢀmethyl styrene and 2ꢀcyclohexenone
are also accomplished, producing the corresponding epoxides with absolute retention of
configuration in 60% and 45% respective yields, and notable levels of enantioselectivity (30 and
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3% ee respectively). The stereoretentive and stereoselective nature of the reactions constitute
strong evidence that the reactions are mediated by selective metal based oxidants, most likely a
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highly electrophilic high valent metalꢀoxo (M =O, M = Fe or Mn) species. For the substrates so
far mentioned we did not find evidence for the formation of kinetically stable hostꢀguest
complexes with 2·M(OTf) , despite being appropriate in size.
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Scheme 3. Cataytic oxidations with Fe and Mn catalysts. a) 2·Fe(OTf) (3 mol %), H O (2.5
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eq.), AcOH (1.5 eq.), MeCN, 0 °C, 30 min. b) 2·Mn(OTf) (1 mol %), H O (2.0 eq.), AcOH (17
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H2N
H2N
a) or b)
2
3
1% (Fe)
3% (Mn)
OH
8c
H2 BF4-
N
BF4-
H2
N
O
a) or b)
2
6
6% (Fe)
8% (Mn)
10
Oxidation of 8c and 10, substrates that do form kinetically stable complexes with the cavitand,
also takes place. Oxidation of 8c occurs selectively at a tertiary C–H bond of the adamantane
core, while epoxidation of 10 occurs at the most remote olefinic site from the ammonium unit. In
both cases, the manganese catalyst exhibits a better performance than the iron analog.
Unfortunately, the selectivity pattern observed in these cases is the same as the one observed
with the parent [M(OTf) (pdp)] (7b·M(OTf) , M = Fe and Mn) catalysts. This suggests that the
2
2
selectivity in these reactions is governed by the innate reactivity of the substrate, and that
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substrate recognition does not have an impact on site selectivity. A supramolecular effect could
potentially favor, for example, oxidation of a secondary C–H bond close in space to the metal
center over a tertiary one which is away from it. Alternatively, it is also possible that oxidation
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occurs at substrate molecules when they are not bound to the cavitand. The combination of
these results thus evidences a powerful catalytic activity of the supramolecular catalysts, but also
limitations in our design that will be addressed in future catalyst generations. Presumably, low
barrier rotation of the pyridylꢀacetal linkage orientates the metal active oxidant towards the
outside of the cavity, preventing synergistic binding and oxidation of the substrate.
We finally assessed the ability of 2·Fe(OTf) to support the formation of high valent ironꢀoxo
2
2
4
species of relevance to nonꢀheme iron oxygenases. Nonꢀheme oxoiron (IV) complexes are
25ꢀ26
highly reactive species which readily engage in C–H oxidation and oxygen transfer reactions.
They are however, more stable than the oxoiron(V) species involved in catalytic C–H and C=C
4
oxidations with H O /AcOH, and have been prepared and studied extensively employing simple
2
2
2
5ꢀ26
coordination complexes.
Nevertheless, their high reactivity is usually non compatible with
elaborated supramolecular scaffolds, which would provide a chemically richer and closer model
to enzymatic sites. Reaction of 2·Fe(OTf) with tetra(nꢀbutyl)ammonium periodate (TBAPI, 1.2
2
equiv., TfOH 1.5 equiv.) was monitored by UVꢀVis, revealing that the ferrous complex is
2+
smoothly converted to a new species [2·Fe(O)] that exhibits a characteristic low energy band
ꢀ1
ꢀ1
26
(
λ = 747 nm, ε = 210 M cm ) of a low spin (S = 1) iron (IV) oxo species (Fig. 4). Indeed,
ESIꢀMS analysis of the complex shows cluster ions at m/z 826.8238 and 1828.5134, consistent
IV
2+
IV
+
with [2·Fe (O)] and {[2·Fe (O)](IO )} cations respectively. The spectrum also shows a peak
3
at m/z = 817.8180 corresponding to an oxidative degradation entailing a formal desaturation
II
2+
reaction ([2·Fe ꢀ2H] . Peaks corresponding to analogous species are observed when
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b·Fe(OTf) is reacted with TBAPI under analogous reaction conditions suggesting that
2
formation of these species does not occur via oxidation of the cavitand. Remarkably, the new
2
+
compound [2·Fe(O)] remains relatively stable at 0 ºC (t1/2 ~ 20 min), but it reacts rapidly
2
7
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(within seconds) with excess thioanisole, producing 0.9 equiv. of the sulfoxide and
regenerating 2·Fe(OTf) (as shown by UVꢀVis spectroscopy, see SI). Overall, this data indicates
2
that the embedment of the complex in the cavitand stands the formation of high valent ironꢀoxo
2
8
species without apparent degradation of the supramolecular vessel, while not compromising its
reactivity in oxygen atom transfer reactions against external substrates.
2
+
Figure 4. Formation of an Fe(IV) oxo species [2·Fe(O)] . Evolution of the UVꢀVis spectra upon
treatment of 2·Fe(OTf) with TBAPI at 0 °C. Inset: ESIꢀMS spectrum of the same reaction
2
mixture.
CONCLUSIONS
We have developed a new deep cavitand receptor functionalized with a chiral
bis(pyridyl)dipyrrolidine ligand directed to metal coordination. The resulting Mn and Fe triflate
derivatives are competent catalysts for the oxidation of CH and C=C bonds with hydrogen
peroxide under mild conditions. The selectivities obtained in the oxidation reactions so far tested
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with substrates that form kinetically stable complexes with the receptor do not significantly
differ from those obtained with a model compound, suggesting that the oxidation steps are
occurring to a significant extent outside the cavity. To the best of our knowledge, this system
represents the first example of a sizeable container functionalized with a coordination complex
0
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capable of a) maintaining catalytic activity in selective C–H/C=C oxidation reactions, and b)
28
supporting high valent metalꢀoxo species typically associated with such transformations. Future
developments in this area will address the limitations of the system presented, including the
development of conformationally restricted analogues which prevented free rotation of the ligand
scaffold. Our synthetic approach holds promise in this regard, since key intermediate 6 could be
derivatized with a number of readily accessible and well established building blocks for the
construction of tetradentate nitrogen ligands oriented towards early transition metal oxidation
4
catalysis.
ASSOCIATED CONTENT
Supporting Information.
Synthetic procedures and characterization data for new compounds. Detailed procedure for
catalytic oxidation reactions. Formation and reactivity of Fe(IV) oxo species. Hostꢀguest studies.
1
D and 2D NMR, HRMS, UVꢀVis spectra. Xꢀray diffraction data for 6 and 2·Fe Cl O.
2 4
AUTHOR INFORMATION
Corresponding Author
*
Eꢀmail: agusti.lledo@udg.edu, miquel.costas@udg.edu
ACKNOWLEDGMENT
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We thank MINECO ꢀ Spanish Government (“Ramón y Cajal” grant RYC2012ꢀ11112 and
CTQ2014ꢀ54306ꢀP to A.L., CTQ2015ꢀ70795ꢀP to M.C.), Generalitat de Catalunya,
(2014SGR931 and 2014SGR862), and Universitat de Girona (MPCUdG2016/096) for financial
support.
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(
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(27) As with other neutral substrates, we did not find any evidence to support the formation of
a kinetically stable hostꢀguest complex with thioanisole.
(28) A recent report describes an iron complex fused to a calixarene from which a highly
IV
unstable Fe (O) is obtained, see:: Ségaud, N.; De Thomasson, C.; Daverat, C.; SénéchalꢀDavid,
K.; Dos Santos, A.; Steinmetz, V.; Maître, P.; Rebilly, J.ꢀN.; Banse, F.; Reinaud, O., Mimicking
the Regulation Step of FeꢀMonooxygenases: Allosteric Modulation of FeIVꢀOxo Formation by
Guest Binding in a Dinuclear ZnII–FeII Calix[6]areneꢀBased Funnel Complex. Chem. Eur. J.
2
017, 23, 2894ꢀ2906.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment
20