Encapsulated N-heterocyclic carbenes in silicones without reactivity modification

Article abstract of DOI:10.1002/anie.200702288

(Chemical Equation Presented) Let them off the leash! Silicone protecting media allow the manipulation and storage of air- and moisture-sensitive N-heterocyclic carbenes (NHCs). Calculations show that a weak carbene-Lewis acid interaction minimizes decomposition of NHCs but does not inhibit NHC reactivity.

Full text of DOI:10.1002/anie.200702288

Communications
DOI: 10.1002/anie.200702288
Encapsulated Reactive Groups
Encapsulated N-Heterocyclic Carbenes in Silicones without Reactivity
Modification**
Fabien Bonnette, Tsuyoshi Kato, Mathias Destarac, GØrard Mignani, Fernando P. Cossío, and
Antoine Baceiredo*
[
1]
N-heterocyclic carbenes (NHCs) are recognized as powerful
tools in organometallic chemistry as ligands for transition
a few encapsulations of reactive species in hydrophobic
[
7,8]
cages,
which can be kept even in water without decom-
[
2]
[9]
metals as well as in organic chemistry as nucleophilic
position, have been reported. Bowden et al.reported that
Grubbs catalysts occluded in a silicone resin can be used for
[
3]
organocatalysts.
[
10]
The deprotonation of air-stable imidazolium salts A using
the metathesis reaction in water.
For NHCs, chemical
strong bases is the most commonly used method to prepare
protection using a Lewis acid is also effective.The stability of
NHC ligands on transition metals B is very well known.
Crabtree et al.recently developed an air- and moisture-stable
NHC–CO adduct C which can be used as a useful precursor
2
[
5]
for the synthesis of NHC complexes. However, in all these
cases, the NHC–Lewis acid interactions are so strong that the
release of the NHC requires thermal activation, and, to our
knowledge, there are no reports concerning the use of these
protected carbenes in organocatalysis.
In this context, we chose the hydrophobic, chemically
resistant polydimethylsiloxane (PDMS) as a matrix to protect
NHCs.In addition, since silicon compounds show weak Lewis
acid character depending on the substituents on silicon, an
additional chemical stabilization effect on NHCs can also be
air-sensitive NHCs.The development of storable precursors
[
4,5]
[6]
of NHCs
or of original methods to more easily generate
NHCs is an active research area.Herein we describe the first
efficient stabilization of NHCs in silicone derivatives, without
any significant modification of the reactivity compared to the
free species.
expected.In fact, a stable hypervalent NHC–SiR complex D,
4
using chlorosilanes with relatively strong Lewis acid character
[
11]
(SiR = SiCl , SiPh Cl ), has been reported.
4
4
2
2
To conserve highly reactive species, two types of protec-
tion (physical and chemical) can be considered.Physical
protection in paraffin oils is the usual method for air-sensitive
compounds, such as alkali metals or metal hydrides.Recently,
Silicones containing NHCs were prepared by two meth-
ods: either by dissolving the NHC in already prepared PDMS
(10 wt%) or through the polymerization of octamethylcyclo-
[12]
tetrasiloxane (known as D ) catalyzed by the NHC itself in
4
the presence of hexamethyldisiloxane (known as M ) as a
2
[
*] Dr. F. Bonnette, Dr. T. Kato, Dr. A. Baceiredo
Laboratoire HØtØrochimie Fondamentale et AppliquØe (UMR 5069)
UniversitØ Paul Sabatier
blocking agent.
The decomposition of NHCs 1a–d in different media was
1
monitored by H NMR spectroscopy in C D (Table 1).The
6
6
118, route de Narbonne, 31062 Toulouse Cedex 9 (France)
results clearly show that simple physical protection of NHCs
by polymeric compounds is not sufficient to conserve the
carbene as indicated by the relatively rapid degradation
Fax: (+33)5-61-55-82-04
E-mail: baceired@chimie.ups-tlse.fr
Dr. M. Destarac
Rhodia Recherches et Technologies
Centre de Recherches et Technologies d’Aubervilliers
(hydrolysis) of the NHC 1a into the iminoformamide 2a in a
chemically inert polymer, such as paraffin (Table 1, entry 9).
In contrast, using PDMS (Table 1, entry 5), or silicone
52 rue de la Haie Coq, 93308, Aubervilliers Cedex (France)
oligomer MD M (Table 1, entry 10), no decomposition was
Dr. G. Mignani
4
Rhodia Recherches et Technologies
observed after one week, and only a slight amount of
hydrolyzed product (2a, 5–8%) was observed after one
month.However, the NHC 1a in hexamethyldisiloxane M2
85 avenue des Fr›res Perret, BP 62,
Saint-Fons, 69192 (France)
Prof. F. P. Cossío
(Table 1, entry 7), which possesses weaker Lewis acid silicon
Departamento de Química Orgµnica I
Universidad del País Vasco-Euskal Herriko Unibertsitatea
Facultad de Química, P. K. 1072,
San Sebastiµn–Donostia (Spain)
centers, decomposes more rapidly (complete hydrolysis after
one week).These results clearly demonstrate the importance
of the chemical protection through a silicon–NHC interaction
for the protection of NHCs.Although carbene 1a is stable to
oxidation, carbenes 1b and 1c are much more reactive.
Particularly, 1c is a highly reactive oily product, which slowly
[
**] We are grateful to the CNRS and RHODIA for financial support of
this work. We also thank SGI/IZO-SGIker UPV/EHU for generous
allocation of computational resources.
[13]
decomposes at room temperature. In fact, 1c, the NHC
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
with the smallest substituents, quickly oxidized in PDMS
8632
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8632 –8635
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Angewandte
Chemie
[
a]
Table 1: Degradation of NHCs 1a–d in different media (%).
[
b]
Entry
2+3 [%]
3
h
5
20 h
48 h
1 w
4 w
[
c]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
9
23
60
20
0
15
2
2
84
95
100
100
1
45
15
25
7
[
c]
c]
1b
13
58
5
[
1c
1d
[
c]
[
d]
1a-PDMS
1c-PDMS
1a-M2
1a-THF
1a-Paraffin
0
3
0
0
0
0
2
81
100
100
13
1
8
[
e]
[
f]
0
0
87
5
[
g]
1
1
1
1
1
1a-MD M
0
4
Ph [h]
1a-MD4
1b-MD4
1c-MD4
1d-MD4
M
0
1
0
12
0
4
0
16
0
5
2
25
0
6
3
100
0
8
8
Ph
M
Ph [i]
M
Ph
M
[a] 1a: R=tBu, 1b: R=cyclohexyl, 1c: R=iPr, 1d: R=Mes=2,4,6-
Me C H . [b] Proportion of decomposed products (2+3) relative to 1
3
6
2
after the times indicated, determined from the intensity of signals in the
HNMR spectrum for 1, 2 and 3. [c] 1a (crystals), 1b (crystals), 1c
1
Figure 1. B3LYP/6-31G*-optimized structures of complexes 5a,b. Bond
lengths are given in Š.
(
distillated oil), 1d (crystals). [d] PDMS=polydimethylsiloxane. [e] M =
2
(
Me Si) O. [f] In this case, the decomposition estimation by NMR
3
2
spectroscopy may not be precise because the NHC solution continually
separated into two phases over the course of the decomposition.
Ph
[
(
g] MD M=Me SiO(SiMe O) SiMe . [h] MD M=Me SiO(Me SiO)6.6-
electrophilic tetrachlorosilane (1.911 Š), indicating a weaker
NHC–silicone interaction. Indeed, the theoretical calcula-
tions indicate the exothermic formation of complexes (5a,b)
4
3
2
4
3
4
3
2
[
11]
MePhSiO)7.1SiMe . [i] Owing to the high volatility of 1c, 26% of 1c
was lost in 4 weeks, which was indicated by the gradual decrease of
intensity of signals for 1c compared to that for silicone oligomers as
3
[17]
with relatively small stabilization energies of 2.6
and
1
measured by in HNMR spectroscopy.
[
17,18]
ꢀ1
5
.4
about 2.8 kcalmol
agreement with the experimental observations.
bond energies in the
kcalmol , respectively.The interaction in 5b is
ꢀ
1 [18]
stronger than that in 5a, in good
(
Table 1, entry 6) to give the corresponding cyclic urea 3c
after one week.Silicones are not only hydrophobic but also
highly gas- (and notably oxygen-) permeable polymers, which
promotes the oxidation rather than the hydrolysis of NHCs.
The situation dramatically changes in the case of the silicone
oligomer MD4 M, which has more Lewis acidic silicon
centers owing to the presence of phenyl substituents.This
oligomer strongly protects the more reactive NHCs 1b,c
Table 1, entries 12 and 13; 8% decomposition after 4 weeks),
and NHC 1a was almost perfectly protected (Table 1,
entry 11).Noteworthy is the absence of protection of NHC
Because of the weak SiꢀC
NHC
complexes, the easy dissociation of complexes of type 5 in
dilute solutions would be expected.In fact, in contrast to the
[
5,19]
relatively inert NHC complexes,
the reactivity of NHCs in
Ph
Ph
silicones (1a-PDMS, 1c-MD4 M) was found to be almost
identical to that of the free NHC 1.To check the reactivity of
1a-PDMS as an organocatalyst, several known organic
[20]
(
reactions catalyzed by NHCs, namely cyanosilylation,
[
21]
transesterification (Scheme 1), and the polymerization of
[
12]
D4 were tested.In all cases, reaction proceeded smoothly
with the conditions previously described, and the resulting
products were obtained in high yields.In the same way, the
Ph
1
d in MD4 M (Table 1, entry 14).Complete decomposition
of 1d occurs within only one week, which is probably due to
the presence of bulky mesityl groups and the less basic
character of 1d (p-accepting groups on nitrogen atoms),
which hamper the silicon–NHC interaction.
To better understand the interaction between NHCs 1 and
silicones, we carried out some DFT and ab initio calcula-
on the binding between NHC 1e and model silicone
oligomers with different substituents (4a: R = Me, 4b: R =
Ph, Figure 1).The structures of the NHC–silicone complexes
a,b are shown in Figure 1.As expected, in both complexes
a,b there is an interaction between the NHC and the silicon
center to give a pentacoordinate silicon atom with much
longer Si–CNHC distances (1.982 and 1.988 Š, bond orders of
.58) than that of the reported NHC complex with more
II [22]
synthesis of NHC–transition-metal complexes of Pd ,
0
[23]
II [24]
Pt , and Rh
were also successfully achieved with 1a-
[12]
Ph
PDMS or 1c-MD4 M, indicating that the silicone polymer
does not perturb the reaction.Moreover, PDMS appears to
be suitable as the protecting media for the preparation of late-
transition-metal complexes, since there are only very few
reported cases where complexes are known to react with
[14,15]
tions
[
25]
PDMS. In all cases, the silicone matrix was easily removed
by washing the resulting complexes with pentane.
5
5
The convenience of stable NHCs in silicone derivatives is
[
16]
Ph
clear, as the mixture (1a-PDMS or 1c-MD4 M) can be
introduced into the Schlenk tube using a spatula in air without
any problem for all the test reactions.
0
Angew. Chem. Int. Ed. 2007, 46, 8632 –8635ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8633
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Communications
Marion, S.Diez-Gonzalez, S.P.Nolan, Angew. Chem. 2007, 119,
046; Angew. Chem. Int. Ed. 2007, 46, 2988.
3
[
4] a) S.Csihony, D .A .Culkin, A .C .Sentman, A .P .Dove, R .M .
Waymouth, J.L. Hedrick, J. Am. Chem. Soc. 2005, 127, 9079;
b) O.Coulembier, A.P.Dove, R.C.Pratt, A.C.Sentman, D.A.
Culkin, L.Mespouille, P.Dubois, R M. .Waymouth, JL. .
Hedrick, Angew. Chem. 2005, 117, 5044; Angew. Chem. Int.
Ed. 2005, 44, 4964.
[
[
[
5] A.M. Voutchkova, L.N. Appelhans, A.R. Chianese, R.H.
Crabtree, J. Am. Chem. Soc. 2005, 127, 17624.
6] D.MØry, J.R.Aranzaes, D.Astruc, J. Am. Chem. Soc. 2006, 128,
5
602.
7] a) D.J. Cram, M.E. Tanner, R. Thomas,
03, 1048; Angew. Chem. Int. Ed. Engl. 1991, 30, 1024; b) R.
Warmuth, Angew. Chem. 1997, 109, 1406; Angew. Chem. Int. Ed.
Engl. 1997, 36, 1347; c) R.Warmuth, M A. .Marvel, Angew.
Angew. Chem. 1991,
1
Chem. 2000, 112, 1168; Angew. Chem. Int. Ed. 2000, 39, 1117.
8] a) M.Yoshizawa, T.Kusukawa, M.Fujita, K.Yamaguchi, J. Am.
Chem. Soc. 2000, 122, 6311; b) M.Yoshizawa, T.Kusukawa, M.
Fujita, S.Sakamoto, K.Yamaguchi, J. Am. Chem. Soc. 2001, 123,
[
[
10454.
9] a) V M. .Dong, D.Fiedler, B.Carl, R G. .Bergman, K N. .
Raymond, J. Am. Chem. Soc. 2006, 128, 14464; b) D.Fiedler,
R.G.Bergman, K.N.Raymond, Angew. Chem. 2006, 118, 759;
Angew. Chem. Int. Ed. 2006, 45, 745.
Scheme 1. Reactions using NHCs in silicones (1a-PDMS and 1c-
Ph
MD4 M). TMS=trimethylsilyl, Bn=benzyl, MS=molecular sieves,
Vi=vinyl, COD=cyclooctadiene.
[10] M.T.Mwangi, M.B.Runge, N.B.Bowden,
006, 128, 14434.
11] Highly electrophilic chlorosilanes, such as SiCl4 and R SiCl ,
J. Am. Chem. Soc.
2
[
2
2
In conclusion, silicone derivatives were found to be an
efficient protecting medium for N-heterocyclic carbenes, and
these derivatives allow moisture-sensitive NHCs to be
handled or stored in air without any special precautions.
More interestingly, this encapsulation is efficient for NHCs
which are usually not stable at room temperature, such as 1c.
In fact, only a weak carbene–Lewis acid interaction (ca.3–
react with NHCs to form pentacoordinate silicon complexes
which are stable even in solution; a) N.Kuhn, T.Kratz, R.
Bläser, R.Boese, Chem. Ber. 1995, 128, 245; also a TiCl complex
4
of a benzannulated NHC has been reported: b) F.E.Hahn, T.
von Fehren, R.Fröhlich, Z. Naturforsch. B 2004, 59, 348.
[
12] This result is strongly related to the absence of any catalytic
activity of 1d for the ring-opening polymerization (ROP) of D4,
which is usually initiated by a nucleophilic attack of the NHC on
ꢀ1
5
kcalmol ) stabilizes NHCs enough for them to be stored
a silicon center of the D monomer.M.Rodriguez, S.Marrot, T.
4
without significant decomposition.Furthermore, the weak-
ness of this interaction does not inhibit the reactivity of the
NHCs.
Kato, S.StØrin, E.Fleury, A.Baceiredo,
2007, 692, 705.
13] T.Schaub, M.Backes, U.Radius, Organometallics 2006, 25, 4196.
14] All the reported calculations were carried out using the B3LYP
J. Organomet. Chem.
[
[
hybrid functional.See: a) W.Kohn, A.D.Becke, R.G.Parr,
Phys. Chem. 1996, 100, 12974; b) A.D. Becke, J. Chem. Soc.
993, 98, 5648; c) A.D.Becke, Phys. Rev. A 1988, 38, 3098.The
basis set used in these calculations was 6-31G*.See: W.J.Hehre,
L.Radom, P.von R.Schleyer, A.J.Pople, Ab Initio Molecular
J.
Received: May 23, 2007
Revised: August 8, 2007
Published online: October 2, 2007
1
Keywords: carbene ligands · density functional calculations ·
.
Orbital Theory, Wiley, New York, 1986, p.76.
15] All calculations were performed using the Gaussian 03 suite of
programs: Gaussian 03, Revision C.02, M. J. Frisch et al., see
Supporting Information.
N-heterocyclic carbenes · silicones · supported catalysts
[
[
16] T.A.Albright, J.K.Burdett, M .- H.Whangbo,
Orbital Interac-
tions in Chemistry, Wiley, New York, 1985, p.272.
[
1] a) D.Bourissou, O.Guerret, F.P.Gabbaï, G.Bertrand,
Rev. 2000, 100, 39; b) A.J.Arduengo, Acc. Chem. Res. 1999, 32,
13; c) F.E. Hahn, Angew. Chem. 2006, 118, 1374; Angew.
Chem.
[
17] This stabilization energy was calculated at the MP2(fc)/6-31G*//
B3LYP/6-31G* + DZPVE level of theory because of problems
that arise with B3LYP in highly substituted systems.See: a) S.
Grimme, Angew. Chem. 2006, 118, 4571; Angew. Chem. Int. Ed.
9
Chem. Int. Ed. 2006, 45, 1348.
[
2] a) W.A. Herrmann, Angew. Chem. 2002, 114, 1342; Angew.
Chem. Int. Ed. 2002, 41, 1290; b) M.C. Perry, K. Burgess,
Tetrahedron: Asymmetry 2003, 14, 951; c) N-Heterocyclic Car-
benes in Transition Metal Catalysis: Topics in Organometalic
Chemistry, Vol. 28 (Ed.: F. Glorius), Springer, Berlin, 2007; d) S.
Diez-Gonzalez, S.P.Nolan, Coord. Chem. Rev. 2007, 251, 874.
3] Recent reviews on the catalytic activity of NHCs: a) D.Enders,
T.Balensiefer, Acc. Chem. Res. 2004, 37, 534; b) V.Nair, S.
Bindu, V.Streekumar, Angew. Chem. 2004, 116, 5240; Angew.
Chem. Int. Ed. 2004, 43, 5130; c) N-Heterocyclic Carbenes in
Synthesis (Ed.: S. P. Nolan), Wiley-VCH, Weinheim, 2006; d) N.
2006, 45, 4460; b) P.R.Schreiner, A.A.Fokin, R.A.Pascal, A.
de Meijere, Org. Lett. 2006, 8, 3635; c) S.Grimme, M.Steinmetz,
M.Korth, J. Org. Chem. 2007, 72, 2118; d) M.D. Wodrich, C.
Corminboeuf, P.R. Schreiner, A.A. Fokin, P.v.R. Schleyer,
Org. Lett. 2007, 9, 1851.
[
[18] Given the large size of structures 4b and 5b (81 and 96 atoms,
respectively), this energy was estimated at the B3LYP/6-31G* +
DZPVE level from the following isodesmic equation: 4a + 5b!
4b + 5a.
[19] C.M.Crudden, D.P.Allen, Coord. Chem. Rev. 2004, 248, 2247.
8634 www.angewandte.org
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Angewandte
Chemie
[
20] J J. .Song, F.Gallou, J T. .Reeves, Z.Tan, N K. .Yee, C H. .
Gelloz, O.Buisine, -J F. .Briꢁre, G.Michaud, S.StØrin, G.
Senanayake, J. Org. Chem. 2006, 71, 1273.
21] a) G.A. Grasa, R.M. Kissling, S.P. Nolan,
Mignani, B.Tinant, J-. P.Declercq, D.Chapon, I .E .Marko,
Organomet. Chem. 2005, 690, 6156.
J.
[
Org. Lett. 2002, 4,
3583; b) G .W .Nyce, J .A .Lamboy, E .F .Connor, R .M .Way-
[24] G D. .Frey, C F. .Rentzsch, D.von Preysing, T.Scherg, M.
mouth, J.L.Hedrick, Org. Lett. 2002, 4, 3587.
Mꢂhlhofer, E.Herdtweck, W A. .Herrmann,
J. Organomet.
[
22] M S. .Viciu, R F. .Germaneau, O.Navarro-Fernadez, E D. .
Stevens, S.P.Nolan, Organometallics 2002, 21, 5470.
23] a) I.E.Markꢀ, S.StØrin, O.Buisine, G.Mignani, P.Branlard, B.
Tinant, J.-P. Declercq, Science 2002, 298, 204; b) G.Berthon-
Chem. 2006, 691, 5725.
[25] S.Caddick, G.F.N.Cloke, Hitchcock, P.B., A.K.de K.Lewis,
Angew. Chem. 2004, 116, 5948; Angew. Chem. Int. Ed. 2004, 43,
5824.
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Angew. Chem. Int. Ed. 2007, 46, 8632 –8635ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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