Encapsulated cobalt-porphyrin as a catalyst for size-selective radical-type cyclopropanation reactions

Article abstract of DOI:10.1002/chem.201400055

A cobalt-porphyrin catalyst encapsulated in a cubic M₈L ₆ cage allows cyclopropanation reactions in aqueous media. The caged-catalyst shows enhanced activities in acetone/water as compared to pure acetone. Interestingly, the M₈L₆ encapsulated catalyst reveals size-selectivity. Smaller substrates more easily penetrate through the pores of the "molecular ship-in-a-bottle catalysts" and are hence converted faster than bigger substrates. In addition, N-tosylhydrazone sodium salts are easy to handle reagents for cyclopropanation reactions under these conditions.

Full text of DOI:10.1002/chem.201400055

DOI: 10.1002/chem.201400055
Communication
&
Homogeneous Catalysis
Encapsulated Cobalt–Porphyrin as a Catalyst for Size-Selective
Radical-type Cyclopropanation Reactions
[a]
[a]
[b]
[b]
´
´
Matthias Otte, Petrus F. Kuijpers, Oliver Troeppner, Ivana Ivanovic-Burmazovic,
Joost N. H. Reek,[a] and Bas de Bruin*[a]
remained unexplored. In addition, and most importantly with
respect of the content of the present paper, it remained un-
clear if size-selective transformations are possible with encap-
sulated catalysts, such as [2-Co@1].
Abstract: A cobalt–porphyrin catalyst encapsulated in
a cubic M8L6 cage allows cyclopropanation reactions in
aqueous media. The caged-catalyst shows enhanced activ-
ities in acetone/water as compared to pure acetone. Inter-
estingly, the M8L6 encapsulated catalyst reveals size-selec-
tivity. Smaller substrates more easily penetrate through
the pores of the “molecular ship-in-a-bottle catalysts” and
are hence converted faster than bigger substrates. In addi-
tion, N-tosylhydrazone sodium salts are easy to handle re-
agents for cyclopropanation reactions under these condi-
tions.
Shape and size selectivity plays a tremendously important
role in several enzymatic processes,[6] as well as a plethora of
catalytic reactions with zeolites,[7] zeolite-like “ship-in-a-bottle”
catalysts,[8] metal–organic frameworks,[9] and related systems.[10]
In marked contrast, homogeneously catalyzed processes with
soluble, caged (supramolecular) catalysts or “molecular ship-in-
a-bottle” systems showing shape or size selectivity are ex-
tremely rare.[11] The development of such systems is of impor-
tance for, among others, the advancement of selective tandem
catalytic processes and/or one-pot, multicomponent reactions
with complex mixtures of catalysts and substrates.
Bio-inspired supramolecular cage catalysts, sometimes referred
to as molecular flasks, attracted much attention in recent
years.[1] The aim of these fascinating man-made architectures is
to translate some of the operational modes of enzymes—na-
ture’s catalysts—to synthetic systems. One of their main char-
acteristics is that catalyzed transformations take place in con-
fined spaces. Unfortunately, the design of such molecular
flasks is very challenging while offering mostly only a very lim-
ited scope of substrates for catalysis. Recently, we have report-
ed the synthesis of the Nitschke-type M8L6 cubic cage
Herein, we present, to the best of our knowledge, the first
example of a soluble “molecular ship-in-a-bottle catalyst” capa-
ble of size-selective radical-type cycplopropanation reactions.
In addition, an unexpected beneficial effect of water on the
rate and selectivity of cobalt–porphyrin-catalyzed cyclopropa-
nation reactions is reported.
We started our investigations by improving the solubility of
cage 1, aiming for a cage that is soluble in different organic
solvents or solvent mixtures. Because modification of the alde-
hyde or porphyrin structure might interfere with the cage for-
mation, we decided to manipulate the counterion.[12] Replacing
Fe(OTf)2 with Fe(NTf2)2 resulted in cage compound 3 in 97%
yield (see the Supporting Information for characterization).
Cage compound 3 proved to be soluble in acetone, acetoni-
trile, and DMF, as well as in solvent mixtures, for example, 1,2-
dichlorobenzene/acetonitrile or water/acetone. In addition,
high-resolution mass spectrometry showed that the stoichiom-
etry of the assemblies does not change in different solvents
(see the Supporting Information). Analogous to compound 1,
cage 3 is also able to encapsulate metalloporphyrins 2-Zn and
2-Co to give [2-Zn@3] and [2-Co@3] in good yields (Scheme 1
and the Supporting Information). Furthermore, compound 3
1
through self-assembly (Scheme 1).[2,3] Furthermore, we
showed that 1 is suitable to encapsulate tetra(4-pyridyl)metal-
loporphyrins (M(TPyP) (2) with M=Zn, Co) to give the M8L6P1
cubic cages [2-Zn@1] and [2-Co@1] (P=porphyrin guest). In
particular, the encapsulation of a cobalt–porphyrin is interest-
ing, because these complexes are known for their catalytic ac-
tivity in radical-type reactions.[4,5] Indeed, we were able to
show that [2-Co@1] is a catalytically active molecular flask.
However, reactions catalyzed by the cubic cage were limited
to DMF as solvent to date. Furthermore, the substrate scope
[a] Dr. M. Otte, P. F. Kuijpers, Prof. Dr. J. N. H. Reek, Prof. Dr. B. de Bruin
Homogeneous and Supramolecular Catalysis Group
Van’t Hoff Institute for Molecular Science (HIMS)
University of Amsterdam (UvA)
1
and [2-Zn@3] were studied by using H NMR diffusion-ordered-
spectroscopy (DOSY) techniques revealing that both com-
pounds behave as single, intact supramolecular entities in so-
lution (see the Supporting Information).
Science Park 904, 1098 XH Amsterdam (The Netherlands)
E-mail: b.debruin@uva.nl
´
´
[b] O. Troeppner, Prof. Dr. I. Ivanovic-Burmazovic
Lehrstuhl fꢀr Bioanorganische Chemie
Department Chemie und Pharmazie
With [2-Co@3] in our hands, we explored its ability to cata-
lyze the cyclopropanation of styrene (4) with ethyl diazoace-
tate (5) in different solvents (Table 1). These experiments
showed that the change of counterion has little effect on the
catalytic synthesis of 6 (Table 1, entries 1 and 2, turnover
Friedrich-Alexander-Universitꢁt Erlangen
Egerlandstrasse 3, 91058 Erlangen (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400055.
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Control experiments showed
that the empty cage 3 is not cat-
alytically active at all (Table 1,
entry 6). Importantly, [2-Co@3] is
substantially more active than
the free tetra-(4-pyridyl)porphy-
rin catalyst 2-Co (entry 7, 3%,
TON=10). Furthermore, water-
soluble
5,10,15,20-tetra-(4-N-
co-
methylpyridyl)-porphyrin
balt(II) tetraiodide (Co-TMePy-
P*4I, 7, Figure 1) and tetrasodi-
um 5,10,15,20-tetra(4-sulfonyl)-
porphyrin
cobalt(II)
(Co-
TPPS*4Na (8), Figure 1) showed
no activity at all under the ap-
plied conditions (entries 8 and
9). It has to be noted that [2-
Co@3] (although soluble in ace-
tone/water mixtures) can mi-
grate to some extend into the
water-insoluble substrate phase.
This means that [2-Co@3] may
act as a phase-transfer catalyst
(with the cyclopropanation cata-
lyst embedded). On the other
Scheme 1. Synthesis of cubic cages 1 and 3 with subsequent encapsulation of 2-M. [2-M@1] is shown as a model
(Spartan 08, MM SYBYL FF; hydrogen atoms and counterions are omitted for clarity).
hand, due to encapsulation in the hydrophobic cavity of [2-
Co@3], substrates might be pulled into the aqueous phase. In-
spired by this, we tested 5,10,15,20-tetra(phenyl)-porphyrin co-
balt(II) (Co-TPP (9), Figure 1). Interestingly, by using catalyst 9
in acetone/water, high yields (75%) of product 6 were ob-
tained already after one hour (d.r.=73:27, TON=302; Table 1,
entry 10). Again, a positive influence of water on the reaction
outcome has been observed when the reaction in pure ace-
tone gave 6 only in 63% (Table 1, entry 11). A possible explana-
tion for this result might be a stabilization of intermediates
through hydrogen bonding from water. Catalyst 10 developed
by Zhang and co-workers is known to be superior to 9 in di-
chloromethane (Figure 1).[15,16] However, in acetone/water the
simpler complex 9 actually outperforms catalyst 10 in terms of
activity (64%, d.r.=79:21, TON=255; Table 1, entry 12). The re-
actions using the apolar catalyst 9 and 10 probably did not
take place in the aqueous phase. Phase separation of the cata-
lyst into the organic-substrate layer might well play a role in
the observed rate enhancements. However, generally reactions
in strongly concentrated solutions (organic solvents) typically
led to lower yields due to enhanced carbene dimerization.
Hence, water does have a true beneficial effect on these reac-
tions. A detailed study of these results is beyond the scope of
the current work. Given these data, explaining the enhanced
rates and higher TONs obtained with [2-Co@3] in acetone/
water mixtures compared with pure acetone is not so straight-
forward, and the effect of water on these reactions requires
more research in the near future. For now, it suffices to state
that the optimal reaction conditions of [2-Co@3] were ob-
tained by performing the reactions in acetone/water mixtures,
by using catalyst loadings of 0.25 mol%.
Table 1. Cobalt-catalyzed cyclopropanation of styrene.
Entry
Catalyst
Solvent[c]
Yield [%]
d.r.[d]
TON
1[a]
2[a]
3
[2-Co@1]
[2-Co@3]
[2-Co@3]
DMF
DMF
DMF
28
25
6
65:35
65:35
65:35
65:35
66:34
—
83:17
—
—
73:27
78:22
79:21
65:35
66:34
33
30
27
77
182
—
10
—
—
302
252
255
292
304
4
5
6
7
8
9
10
11
12
13[b]
14[b]
[2-Co@3]
[2-Co@3]
3
2-Co
7
8
9
9
acetone
19
46
—
3
—
—
75
63
64
73
76
acetone/water
acetone/water
acetone/water
acetone/water
acetone/water
acetone/water
acetone
acetone/water
acetone/water
acetone/water
1:5
1:5
1:5
1:5
1:5
1:5
10
[2-Co@3]
[2-Co@3]
1:5
1:5
1:5
[a] Catalyst loading (0.8 mol%),
4 (1.2 equiv). [b] Reaction time 24 h.
[c] [D6]acetone was used. [d] d.r.=diastereomeric ratio.
number (TON)=33 and 30, respectively).[13] Reducing the cata-
lyst loading to 0.25 mol% resulted in a decreased yield of only
6% and a similar TON of 27 (entry 3). However, employing
[D6]acetone as solvent increased the yield to 19% (Table 1,
entry 4, TON=77). Remarkably, the reactivity of [2-Co@3] in-
creased further by carrying out the reaction in a 5:1 mixture of
water and [D6]acetone giving 46% 6 (Table 1, entry 5, TON=
182).[14]
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With the above-described reaction conditions opti-
mized for the caged catalyst [2-Co@3], we explored
the scope of suitable alkenes as substrates
(Scheme 2). We started our investigations testing di-
verse styrene derivatives. Styrenes with electron-do-
nating groups gave the corresponding cyclopropanes
in high yields (11, 75%, TON=302, d.r.=77:23; 12,
88%, TON=351, d.r.=76:24). Styrenes with electron-
withdrawing substituents also react smoothly, giving
cyclopropanes 13 and 14 in good to high yields (13,
78%, TON=320, d.r.=82:18; 14, 66%, TON=265,
80:20). 2-Vinylnaphtalene is also a suitable substrate
leading to 15 in 69% yield, whereas sterically de-
manding cyclopropane 16 was only obtained in 18%
yield. The lower yield could be an indication that it is
more challenging to assemble the bulky styrene and
5 in the cavity of [2-Co@3]. Another possible reason
might be a substrate or product inhibition due to p
stacking. However, compound [2-Co@3] still reached
a TON of 73. Cyclopropanation of other alkenes by
Figure 1. Structures of catalysts Co-TMePyP*4I (7), Co-TPPS*4Na (8), CoTPP (9), and 10.
Using [2-Co@3] as catalyst for a prolonged reaction time of
24 h resulted in a higher TON of 292 and gave 73% 6 (Table 1,
entry 13). Reducing the temperature to 508C gave similar re-
sults, showing that the reaction can be performed under
milder conditions (entry 14, 76%, TON=304).
using catalyst [2-Co@3] was less successful. Using phenyl or
methyl methacrylate as substrates gave 17 and 18 in moderate
yields (17, 25%, TON=100, d.r.=82:18; 18, 20%, TON=82,
d.r.=53:47). Unsubstituted acrylates, such as n-butyl acrylate
reacted through a [3+2]-cycloaddition giving 1H-pyrazoles
(not shown). Simple olefins, such as 1-octene and allylbenzene
gave cyclopropanation products in low yields of 5% or less
(see 19 and 20).
Next, we focused on studying the scope of diazo com-
pounds in the cyclopropanation of styrene 4 (Scheme 3).
Scheme 3. Substrate scope of diazo compounds suitable for [2-Co@3]-cata-
lyzed cyclopropanation of 4.
Benzyl diazoacetate gave cyclopropane 21 in 72% yield. This
result is similar to ethyl diazoacetate 5, which gave 6 under
the same conditions in 76% yield. Using the bulky tert-butyl di-
azoacetate (27) resulted in the formation of 22 in only 22%.
This matches the results described in Scheme 2, in which the
bulky 4-benzhydrylstyrene gave low yield of 16 in comparison
to other substrates. Disubstituted diazo compounds seem to
be unreactive towards [2-Co@3].
Formation of the rather bulky products, such as 22, showed
that the large cavity of [2-Co@3] is still accessible for rather
large substrates, but the rather low yields obtained also sug-
gest that the cage may well allow size-selective reactions. We
Scheme 2. Substrate scope of alkenes suitable for [2-Co@3]-catalyzed cyclo-
propanation with 5. [a] [D6]acetone/water (2:5).
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further investigated this aspect through competition experi-
ments between different styrenes (Table 2). Initially, we chose
styrene 4 and 4-benzhydrylstyrene 24 as substrates and em-
ployed the optimized reaction conditions while using same
amounts of alkenes (in total, 2 equiv) and one equivalent of 5.
Indeed, [2-Co@3] clearly favors the formation of 6 over 16
(70:30; Table 2, entry 1). Changing the bulky styrene to 25
gave cyclopropanes 6 and 26 in a similar ratio (64:36; entry 2).
However, using the bulky diazo compound 27 as substrate re-
sulted in an increased selectivity towards the less bulky prod-
uct 22 (Table 2, 22/28 79:21; entry 3). To the best of our knowl-
edge, these are the first reported size-selective cobalt–porphy-
rin-catalyzed cyclopropanation reactions. Furthermore, it is
a rare example of a size-selective homogeneous catalysts.
Earlier reports, using different diazo substrates, showed that
catalytic substrate activation took place inside the cavity of
these type of molecular flasks, thus leading to different selec-
tivities compared to similar but non-encapsulated catalysts.[3]
In good agreement, the results described in this paper show
that [2-Co@3] allows size-selective substrate transformations.
This is most easily explained by a slower migration of larger
substrates through the pores of the cage compared to smaller
substrates (Figure 2).[17] As such, the pores of the molecular
flask surrounding the cobalt catalyst in [2-Co@3] make it possi-
ble to distinguish between substrates of similar reactivity but
different size. It is important to note that Co-TPP (9) is not able
to distinguish between these same substrates (Table 2, en-
tries 4–6).
Because the number of stable diazo compounds is limited,
and since diazo compounds are partly toxic and explosive, we
further became interested in using precursors, which are safe
to handle. N-Tosylhydrazone sodium salts seemed promising to
us, because they are easily accessible from aldehydes while
being water soluble. Indeed, styrene 4 could be cyclopropanat-
ed by using N-tosylhydrazone 29 giving 30 in moderate yield
(Scheme 4; 33%, TON=132, d.r.=73:27).
Table 2. Competition experiments.
Scheme 4. Cyclopropanation of 4 with N-tosylhydrazone sodium salt 29.
In conclusion, we have synthesized a new molecular flask [2-
Co@3], soluble in different solvents and solvent mixtures, in-
cluding water/acetone. Employing water/acetone mixtures as
the solvent increased the catalytic performance of [2-Co@3] in
styrene cyclopropanation reactions dramatically. The caged cat-
alyst [2-Co@3] showed a preference for cyclopropanation of
styrenes over other vinylic substrates. While exploring the sub-
strate scope, it became clear that [2-Co@3] is a size-selective
catalyst showing preference for cyclopropanation of smaller
styrene and diazo substrates. Bulky substrates reacted slower
than smaller ones, thus allowing size-selective competition re-
actions. To the best of our knowledge, [2-Co@3] is the first
well-documented homogeneous catalyst capable of size-selec-
tive radical-type cycplopropanation reactions. Furthermore, it
is a rare example of a “molecular ship-in-a-bottle” catalysts. Fi-
nally, we showed that N-tosylhy-
Entry[a]
Catalyst
Styrene
Diazo
Products
Product ratio
c/d
a
b
c
d
1
2
3
4
5
6
[2-Co@3]
[2-Co@3]
[2-Co@3][b]
9
9
9[b]
4
4
4
4
4
4
24
25
25
24
25
25
5
5
27
5
5
27
6
6
22
6
6
22
16
26
28
16
26
28
70:30
64:36
79:21
50:50
49:51
49:51
[a] Catalyst loading (0.25 mol%),
(1.0 equiv), diazo compound 5 or 27 (1.0 equiv), reaction time 24 h, 508C,
in [D6]acetone/water (1:5). [b] Catalyst loading (0.5 mol%).
4 (1.0 equiv), styrene 24 or 25
drazone sodium salts are useful
diazo precursors in [2-Co@3]-cat-
alyzed reactions in aqueous
media.
Experimental Section
To an oven-dried Schlenk flask
were added [2-Co@3] (35 mg,
2.5 mmol), [D6]acetone (0.50 mL),
and deionized water (2.50 mL).
Argon was bubbled 3 min through
Figure 2. Schematic representation of the proposed pore-size-controlled, size-selective transformations catalyzed
by “molecular ship-in-a-bottle” [2-Co@3].
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the reaction mixture. Compounds 4 (1.0 mmol; 104 mg) and 5
(1.0 mmol; 114 mg) were added, and the reaction mixture was
stirred for 24 h in an oil bath at 508C. The mixture was cooled to
RT, and acetone (5 mL) was added. The solvents were removed
under reduced pressure, and the crude product was purified by
column chromatography to give 6 (145 mg, 760 mmol, 76%, d.r.
(trans/cis 66:34).
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Financial support from the Netherlands Organization for Scien-
tific Research (NWO-CW VICI project 016.122.613), the Europe-
an Research Council (ERC grant agreement 202886-CatCIR),
and the University of Amsterdam. M.O. gratefully acknowl-
edges the Alexander von Humboldt Foundation for a Feodor
Lynen postdoctoral fellowship. I.I.-B. and O.T. gratefully ac-
knowledge support through the “Solar Technologies Go
Hybrid” initiative of the State of Bavaria. Dr. Nanda D. Paul is
gratefully acknowledged for providing compound 29. Henk
Kleijn is acknowledged for technical support.
˘
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Keywords: cobalt
·
cyclopropanation
·
homogeneous
catalysis · molecular flasks · porphyrins · radical chemistry
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134, 19981–19984.
[16] For example, see: S. Zhu, J. A. Perman, X. P. Zhang, Angew. Chem. 2008,
120, 8588–8591; Angew. Chem. Int. Ed. 2008, 47, 8460–8463.
[17] Partial and reversible opening of the supramolecular assembly cannot
be fully excluded (e.g., involving reversible imine hydrolysis and/or bipy
dissociation from the Fe corners). This would alter the pore sizes of [2-
Co@3] during catalysis, and hence might facilitate the entrance of
larger substrates into the cage (and product release from the cage)
leading to a lower size selectivity than in the absence of reversible
cage opening.
´
´
[3] M. Otte, P. F. Kuijpers, O. Troeppner, I. Ivanovic-Burmazovic, J. N. H.
Reek, B. de Bruin, Chem. Eur. J. 2013, 19, 10170–10178.
[4] Examples of cobalt–porphyrin catalyst reactions: a) J. V. Ruppel, R.
Kamble, X. P. Zhang, Org. Lett. 2007, 9, 4889–4892; b) Y. Chen, J. V.
Ruppel, X. P. Zhang, J. Am. Chem. Soc. 2007, 129, 12074–12075; c) N. D.
Paul, A. Chirila, H. Lu, X. P. Zhang, B. de Bruin, Chem. Eur. J. 2013, 19,
Received: January 6, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Homogeneous Catalysis
M. Otte, P. F. Kuijpers, O. Troeppner,
´
´
I. Ivanovic-Burmazovic, J. N. H. Reek,
B. de Bruin*
&& – &&
Encapsulated Cobalt–Porphyrin as
a Catalyst for Size-Selective Radical-
type Cyclopropanation Reactions
Molecular ship-in-a-bottle: A cobalt–
porphyrin catalyst encapsulated in
a cubic M8L6 cage allows cyclopropana-
tion reactions in aqueous media. The
caged catalyst showed enhanced activi-
ties in acetone/water as compared to
pure acetone. Most remarkably, the
M8L6-encapsulated catalyst acts as a solu-
ble, size-selective homogeneous “molec-
ular ship-in-a-bottle” catalyst (see
scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!