The efficient copper(I) (hexabenzyl)tren catalyst and dendritic analogues for green "click" reactions between azides and alkynes in organic solvent and in water: Positive dendritic effects and monometallic mechanism

Article abstract of DOI:10.1002/adsc.201100449

An easily synthesized, copper(I) (hexabenzyl)tren complex 1 is an efficient catalyst for the copper(I)-catalyzed Huisgen-type 1,3-cycloaddition between azides and alkynes (CuAAC) reaction in toluene. Alternatively, a convenient procedure involves mixing c

Full text of DOI:10.1002/adsc.201100449

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DOI: 10.1002/adsc.201100449
The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic
Analogues for Green “Click” Reactions between Azides and
Alkynes in Organic Solvent and in Water: Positive Dendritic
Effects and Monometallic Mechanism
Liyuan Liang,a Jaime Ruiz,a and Didier Astruca,*
a
Univ. Bordeaux, ISM, UMR CNRS 5255, 351 Cours de la Libꢀration, 33405 Talence Cedex, France
E-mail: d.astruc@ism.u-bordeaux1.fr
Received: May 31, 2011; Published online: December 9, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100449.
Abstract: An easily synthesized, copper(I) (hexaben- metallodendritic Cu(I) derivatives 2 and 3, the den-
zyl)tren complex 1 is an efficient catalyst for the cop- dritic frame brings about steric protection against
per(I)-catalyzed Huisgen-type 1,3-cycloaddition be- the well-known inner-sphere aerobic oxidation of
tween azides and alkynes (CuAAC) reaction in tolu- Cu(I) to bisACTHUNRTGNE(GNU m-oxo)-bis-Cu(II). The metallodendrim-
ene. Alternatively, a convenient procedure involves ers 2 and 3 are also sometimes more efficient than
mixing copper(I) bromide (CuBr) with hexabenzyl- the parent catalyst, as shown by kinetic studies. Cat-
ACHTUNGTRENNUNGtren and the substrates in toluene which gives, for in- alysis in water without co-solvent of the CuAAC re-
stance, 100% yield of triazole in 10 min using actions of water-insoluble substrates was achieved
0.1 equiv. catalyst with phenylacetylene and benzyl under ambient conditions in good yields with the re-
azide at room temperature. The toluene-soluble cata- cyclable catalyst 5. Efficient catalysis of the CuAAC
lyst 1 is recyclable and is applied, for example, to the reaction by these bulky Cu(I) metallodendrimers
CuAAC synthesis of an 81-branched dendrimer that emphasizes the monometallic mechanism. The differ-
previously required the use of a stoichiometric ence of kinetic behavior between 1 and CuBr+hexa-
amount of copper(II) sulfate (CuSO4)+sodium as- benzyltren suggests, however, that whereas a mono-
corbate “catalyst”. Dendritic copper(I)-centered ana- metallic mechanism is working for 1, the mixture of
logues 2 and 3 of the first and second generations CuBr+hexabenzyltren might involve the bimetallic
(G1 and G2, respectively) containing respectively 18 mechanism proposed by Fokin and Finn.
and 54 branch termini, including a 54-branched
water-soluble metallodendrimer 5, are also very effi- Keywords: alkynes; azides; catalysis; click chemistry;
cient catalysts for the CuAAC reaction. With the copper; mechanism; metallodendrimers; water
Introduction
drimer induces a favorable catalytic effect.[3] As
shown by these seminal studies, intradendritic cataly-
Dendrimers are useful supports for catalysis, because sis is indeed promising, because the dendrimer interi-
they allow high catalyst loading at the periphery of or can function as a complex supramolecular nano-
the dendritic framework and subsequent recycling.[1] reactor whereby the key-and-lock principle, in addi-
Intradendritic catalysis is also intriguing, because the tion to the steric protection, might provide biomimet-
metal centers are then protected by the dendrimer, al- ic conditions.[4]
though the steric bulk of the dendrimer frame often
results in a kinetic drop. This latter strategy has been is Cu(I) catalysis, because oxygen from air binds
successfully developed in particular by Crooks who Cu(I) to form m-peroxo-dicopper(II), then bis(m-oxo)-
A dramatic example of the need of steric protection
AHCTUNGTRENNUNG
demonstrated the use of the dendrimer as a nanoreac- dicopper(II). Thus the unprotected Cu(I) complexes
tor in which the periphery plays the role of a nanofil- are very air-sensitive, which inhibits catalysis.[5] The
ter,[2] and by Frꢀchet with intradendritic organic reac- Cu(I)-catalyzed Huisgen-type 1,3-cycloaddition be-
tions for which a radial polarity gradient in the den- tween azides and alkynes (CuAAC)[6–9] has become
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
one of the most convenient and popular “click” reac- volved in the transition state and requiring some par-
tions to link organic and bio-organic fragments[10] fol- tial decoordination of polydentate nitrogen ligand.[13]
lowing the independent finding of the efficiency of
Following our interest for metallodendritic cata-
Cu(I) catalysis by the groups of Meldal and of Fokin lysts[17] and the frequent use of click reactions in the
and Sharpless.[6] The catalytically active Cu(I) species synthesis of nanomaterials (dendrimers[18] and gold
is usually generated from CuSO4 and sodium ascor- nanoparticles[19]), we have now designed dendritic li-
bate in excess, a very convenient system initially re- gands for catalysts of the click reaction with benzyl
ported by the Fokin–Sharpless group that works well substituents on the nitrogen atoms of tren. Thus, we
in aqueous solvents.[7] Various genuine Cu(I) catalysts are reporting here the new parent catalyst [Cu(I)-
that do not require a sacrificial reductant are also tren(Bn)6][Br] (1) and the dendritic derivatives 2, 3
known, the advantage of liganded Cu(I) being the and 5 containing, as a core, the framework of 1 and
rate acceleration provided by various polyamine li- dendritic substituents located in the para position of
gands.[11] Efficient accelerating ligands are the tris- the phenyl groups of 1. This series of CuAAC cata-
ACHTUNGTRENNUNG
(pyrazolylmethyl)amines,[12] discovered by the Fokin– lysts includes a water-soluble metallodendritic catalyst
Sharpless group, and more recently improved with 5 for CuAAC reactions in water. The catalyst 1 will
the closely related tris(2-benzimidazolylmethyl)- turn out to be of great interest for its efficiency per se,
ACHTUNGTRENNUNG
amines reported by the Finn group.[13] We have been ease of preparation, solubility in toluene and recycling
interested in the simple, commercial ligand properties, and a comparison will be carried out with
N(CH2CH2NH2)3, abbreviated as tren. The Cu(I) the catalytic properties of the metallodendrimers.
complex
of
the
hexamethyltren
ligand
N(CH2CH2NMe2)3 (Me6tren) has been shown by Ma-
tyjaszewskiꢂs group[14] to be an efficient catalyst for Results
the click reactions. Matyjaszewski et al. have com-
pared various polyamine ligands and shown that the Synthesis and Characterization of [Cu(I)tren(Bn)6]
Me6tren ligand provided a 50-fold increase of the [Br] (1) and Dendritic Analogues
click rate constant compared to CuBr. Recently, the
complex [Cu(I)trenACTHNUTRGNEUNG
(C18H37)6][Br][15] 4 has also been The hexabenzyltren ligand was easily synthesized by
probed for its efficiency. Dendritic protection of the refluxing commercial tren with benzyl bromide in ace-
Cu(I) center, however, is a rational strategy that in- tonitrile in the presence of K2CO3, and the Cu(I)
volves intradendritic catalysis and has not been ad- complex 1 was then also easily obtained by heating
dressed so far. Yet, supramolecular effects involving CuBr with the hexabenzyltren ligand in dioxane at
weak bonds are well known in dendrimer chemistry[16] 608C overnight (Scheme 1). The complex 1 is well
and are likely to play a role because of the interac- soluble in toluene, which is very practical for click re-
tions, besides coordination, that influence the catalytic actions, because the 1,2,3-triazole products precipitate
reaction pathway within the metallodendrimer interi- from this solvent, and it is then easily separated from
or. An additional interest in sterically protecting the the reaction products by filtration. Both the ligand
catalytic Cu(I) center is to check whether a monome- and the complex 1 were characterized inter alia by the
tallic mechanism is viable for this click reaction and molecular ion peaks in their MALDI-TOF mass spec-
to search for information provided by the dendritic trua,
UV-vis.
spectroscopy
(l=316 nm,
e=
effects on the catalysis. Indeed, fine studies have 2689.8 Lmolꢀ1 cmꢀ1), cyclic voltammetry {electro-
pointed out the complexity of the mechanism, and in chemically irreversible oxidation at Epa =0.30 V vs.
particular the implication of several Cu species in- [FeACTHNUTRGNEUNG
(C5Me5)2]+/0 on Pt in CH2Cl2, using 0.1M [(n-
Scheme 1. Synthesis of the complex [Cu(hexabenzyl)tren][Br] (1).
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Scheme 2. Syntheses of the tren ligands G1 and G2 and structures of their CuBr complexes 2 (G1) and 3 (G2).
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
Bu)4N]
0.40 V} and elemental analysis.
The dendritic analogues 2 and 3 of 1 were designed taining three triethylene glycol termini.
ACHTUNGTRENNUNG
by introducing dendrons in the para-position of
Finally, the Cu(I) catalysts 2, 3 (Scheme 2) and 5
benzyl bromide.[20] Thus, dendrons containing 3 allyl (Figure 1) were prepared by heating CuBr with these
termini for the first generation and 9 allyl termini for dendritic tren ligands G1, G2 and G’2 in freshly dis-
the second generation (with 1!3 connectivity)[21] tilled dioxane at 608C overnight. These ligands and
were linked to the tren amino groups via their bromo- the metallodendritic catalysts 2, 3 and 5 were charac-
benzyl focal points, resulting in the formation of den- terized by H and 13C NMR, UV-vis. spectroscopy and
1
dritic ligands that contain 18 and 54 terminal groups elemental analysis, and the sizes of the ligands were
for the first and second generations G1 and G2, re- determined by DOSY NMR (1.92 nm for G1) and dy-
spectively (Scheme 2).
namic light scattering (4.1 nm for G2). As it is often
The water-soluble dendritic tren ligand 9 (G’2) con- the case for relatively large dendrimers, the elemental
taining 27 triethylene glycol termini was synthesized analyses show slightly lower found values, due to the
according to Scheme 3 by a ꢃclickꢂ reaction between encapsulation of residual water and inorganic salts.
Scheme 3. Synthesis of the G’2 dendron 9.
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Figure 1. Structure of the water-soluble dendritic Cu(I) catalyst 5 (from the G’2 dendron 9+CuBr; see Scheme 3 for the syn-
thesis of the G’2 dendron 9).
This trend is more marked, however, for the dendri- kynes are completely unreactive. In Table 1, the
mer 5 terminated by triethylene glycol termini.
yields with the new Cu(I) catalysts are compared to
those obtained in the present study using the known
catalyst [Cu(I)trenACHTNURGTEN(UNG C18H37)6][Br], 4 under the same
Catalysis of the Click Reaction in Toluene by the
Cu(I) Complexes 1–4
conditions and with those obtained in the absence of
catalyst. The yields recorded at 0.1% mol catalyst per
mol substrate allow a differentiation of the efficien-
The CuAAC reactions between various terminal al- cies of the various catalysts with various substrates
kynes and azides catalyzed by the dendritic catalysts and reaction conditions. All the reactions of Table 1
1–4 proceed quantitatively or in high yields using only were also carried out using 1% mol of catalyst 1 at
0.1% catalyst under various conditions. Internal al- 228C, and these reactions were quantitative or nearly
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
Table 1. Compared yields and selectivities of CuAAC reactions catalyzed by 0.1 mol% equiv. dendritic and non-dendritic
complexes Cu(I)ACHTUNGTRENNUNG(tren)Br and without catalyst.
N8 R1 R2
s
T [8C] t [h] Cat. 1[a]
Product [%][b]
Cat. 2[a]
Cat. 3[a]
Cat. 4[a]
No catalyst[a]
Product [%][b]
Product [%][b]
Product [%][b]
Product [%][b]
M
S
T
M
S
T
M
S
T
M
S
T
M
S
T
1
2
3
4
5
6
7
8
9
Bn Ph
Bn Ph
Bn Ph
Bn Ph
Bn Ph
t
t
n
n
p
t
t
t
t
t
60
22
60
22
22
22
60
60
60
60
22
60
60
60
60
24
24
14
24
48
24
24
24
72
14
24
24
24
72
24
100
100c
100
100
–
0
0
0
0
–
1
0
2
0
100 99
100 100
100 99
100 100
1
0
1
0
0
1
0
1
0
100 100
100 81
100 100
100 95
100 94
0
0
0
0
0
8
1
2
0
9
4
2
0
0
7
100 83
81 71
100 100
0
0
0
0
0
8
2
1
0
83
71
100
85
80
46
48
41
100
28
3
31
0.4 0.2 0.6
7
1
1
13
2
29
0
3
1
0
4
1
1
0
21
7
3
0
0
11
10
2
1
17
3
30
0
79
29
16
13
0
95
94
85
80
–
100
Bn CO2Et
Bn n-Bu
Bn SiMe3
Bn Fc
99
100 91
100 100
100 60
93 100
92
100 91
61 78
100 99
92
100 38
100
98[d]
93
90
98
92
80
99
46
40
100
10 R3 CO2Et
11 R3 CO2Et
12 R3 CH2OH
13 R3 R4
10 100 90
10 100 91
100 78
100 50
100 93
22 100 58
t
t
t
t
2
3
0
0
1
100 97
100 98
100 100
100 97
100 85
3
2
0
0
6
100 96
100 98
100 97
8
2
0
0
58
95
96
88
22
13
13
0
97
100[d]
100[d]
99[d]
97
96
14 R3 R5
15 Ad CO2Et
97
91
100
93
100 88
100 72
t
12 84
41
52
[a]
1 mmol of each reactant and 0.1% mmol of the catalysts were used for the click reaction in 1 mL solvent when toluene
or pentane was used.
[b]
[c]
Determined by GC, two runs, ꢁ3%. Isolated yields are 1% to 10% lower. The turnover numbers (TONs) are ten times
larger than the yields%.
In the presence of sodium ascorbate (2 equiv per mol catalyst).[d] 1% of cat. 1 was used. Cat. 4: [Cu(I) tren
ACHTNUGTRNE(UNG C18H37)6]
[Br].[15] Fc=ferrocenyl. s=solvent, t=toluene, p=pentane, n=neat, M=major product; S=side product (minor 1,5-
isomer), T=total product, R3 =m-MeBn; R4 =p-CH3OC6H4; R5 =p-CHOC6H4.
so without formation of the minor triazole isomer. Table 2. Recharging of both dendritic catalysts 2 and 3
(PhCCH+BnN3, 0.1 mol% catalyst, toluene, 608C, 24 h).
The yields obtained with 0.1% mol catalyst are most
of the time significantly higher with the dendritic cat-
alysts than with the non-dendritic catalysts 1 and 4. In
the case of the catalyst 1, this may eventually be due
to its air sensitivity, and these yields could be slightly
but significantly increased upon using 0.1% mol
sodium ascorbate in order to inhibit catalyst oxida-
tion. This advantage of the dendritic catalysts 2 and 3
over the non-dendritic analogues 1 and 4 is more
marked for the reactions carried out at 228C than at
608C. In some cases, the catalyzed reaction with the
G1 dendritic complex 2 produces better yields than
Recharging run[a]
1
2
3
4
5
6
7
8
9
10
Catalyst 2 (yield
[%])[b]
98 98 95 98 99 99 95 96 93 91
99 99 97 98 98 97 89 82 83 84
Catalyst 3 (yield
[%])[b]
[a]
Recharging the catalyst for the reaction of entry 1,
Table 1.
ꢁ3%.
[b]
G2, 3, and in some others it is the opposite. Thus it ꢀ188C of the toluene-insoluble reaction product and
appears that at least at 228C the dendritic catalysts re-used giving a quantitative yield of product upon re-
are selective for some substrates, although this aspect cycling 1 three times and recycling 2 twice. On the
is leveled off when reactions are carried out at 608C other hand, the result was less successful for 3, possi-
and for a sufficient amount of time at 0.1% catalyst bly for solubility reasons (Table 3).
vs. substrate (TON values equal or close to 1000).
A convenient alternative consists in using a mixture
The catalysts 2 and 3 could be recharged with the of CuBr+hexabenzyltren in toluene instead of 1. For
substrates of entry 1 at least ten times (Table 2), instance, using 10% mol of this catalyst yielded 100%
giving high yields of products, which increased the yield of the triazole 1,4-isomer in 10 min at room tem-
turnover numbers to close to 104.
perature with phenylacetylene and benzyl azide. With
Alternatively, the Cu(I) catalyst could be recycled, 0.1% mol of this amount vs. substrates, a quantitative
even with only 0.1% mol catalyst, by filtration at yield was obtained at 228C in 24 h including the for-
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ꢂ
Table 3. Yields of the CuAAC reactions between PhC CH
and BnN3 using 0.1% mol of catalyst 2 and 3, and 1% mol
of catalyst 1 in toluene at 228C.
catalyst 1 is a good protection against the risk of aero-
bic oxidation of this catalyst.
It is important to note that at 608C the non-cata-
lyzed reaction is efficient when the substituent on the
alkyne is electron-withdrawing (CO2Et), yields being
even sometimes close to quantitative (entry 10 of
Table 1). The non-catalyzed reaction is not very selec-
tive, unlike the catalyzed reaction, but again the selec-
tivity of the non-catalyzed reaction increases upon de-
creasing the temperature. For instance with R3 and
Run[a]
Cat. 1
Cat. 2
Cat. 3
Product [%]
Product [%]
Product [%]
M
S
M
S
M
S
1
2
3
100
100
100
0
0
0
100
100
91
0
0
0
81
41.7
30
0
0
0
M=major product; S=side product (minor 1,5-triazole R2 =CO2Et in toluene, the ratio of major isomer/
[a]
isomer).
minor isomer is 2.8 with 100% yield at 608C but is
raised to 3.5 with 77% yield at 228C. This non-cata-
lyzed reaction also occurs at 608C, but to a lesser
mation of only 0.7% of minor isomer (compare extent when the alkyne substituent is phenyl (entry 1
entry 2 of Table 1, no trace of minor isomer), whereas of Table 1) than when it is the electron-withdrawing
the same reaction without ligand (CuBr alone) pro- substituent CO2Et.
duced an 18% yield of the major isomer and 1% of
the minor 1,5-isomer.
A kinetic study was carried out for the four cata-
lysts 1–4 under the conditions of entry 1 of Table 1
ꢂ
Table 1 also shows the formation of a minute (0.1% mol catalyst, 228C, PhC CH+BnN3). The
amount of the minor 1,5-triazole isomer, this isomer plots of the inverse of the concentrations as a function
being formed in larger amounts, as it is known, in the of time (Figure 2) show that the reactions catalyzed
non-catalyzed reactions. In order to investigate the in- by the metallodendritic catalysts 2 and 3 are faster
fluence of the amount of catalyst not only on the re- than those carried out using the non-dendritic cata-
action yields, but also on the selectivity, the CuAAC lysts 1 and 4, the fastest reaction being observed with
reaction has been carried out using lower amounts of the 54-branch dendrimer G2 in the case of these sub-
catalysts, and the selectivities and yields are given in strates. The mixture of CuBr+hexaACTHUNTGRNEUNG(benzyl)tren gives
Table 4. The reaction giving the largest amount of a faster kinetics than the isolated catalyst 1 (vide
minor isomer in the catalyzed reaction and the best infra, Discussion section). The mixture of CuBr+den-
yield of the non-catalyzed reaction were selected as dron G1 gives slow kinetics, and it is noticed that
examples. Table 4 shows that when the amount of cat- CuBr is solubilized much more slowly in toluene with
alyst is decreased there is a mixture of the catalyzed dendron G1 than with hexa
ACHTUNGTREN(NUNG benzyl)tren.
and non-catalyzed reactions. This selectivity was re- In these reactions, the yields were quantitative for
corded in the less favorable case as indicated above, cat. 2 and high for the other catalysts after 20 h. It
ꢂ
but for instance with PhC CH, the yield was quanti- was suspected that these uncompleted reactions were
tative without formation of any trace of the minor
isomer with only 0.01% mol catalyst 1 vs. substrates
in the presence of sodium ascorbate. The effect on
the selectivity of the aerobic sensitivity of catalyst 1 is
also all the more hazardous as its amount is lower,
but the addition of one mol sodium ascorbate vs. the
Table 4. From catalyzed to non-catalyzed reactions: influ-
ence of the variation of the concentration of the catalyst 1
on the selectivity of the reaction between m-MeBnN3 and
HCC
ACHTUNGTRENNUNG(CO2Et) at 100% total yield (608C).
Mol% of 1 vs. Time Main prod- Minor
Selectivity
substrates
[h]
uct [%]
isomer [%]
1
0.1
16
15
15
45
48
48
72
99
90
85.6
75.6
73.5
71
1
10
14.4
24.4
26.5
29
99
9
0.01
0.001
0.0005
0.00001
0
5.9
3.1
2.8
2.4
2.2
Figure 2. Compared kinetics of the CuAAC reaction be-
tween PhCCH and BnN3 at 228C in toluene using with
0.1% catalysts 1–4 or CuBr+tren ligand. A CuBr+(ben-
zyl)6tren; B: CuBr+tren dendron G1.
69.2
30.8
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
due to aerobic oxidation of the catalysts used in very by 0.1% CuSO4 +sodium ascorbate was carried out
low amounts. Thus the reaction catalyzed by 1 was between benzyl azide and phenylacetylene on water
also carried out in the presence of two equiv.of under N2 at 228C for 24 h and yielded 5% of triazole
sodium ascorbate per mol catalyst. The kinetics was product.
exactly the same in the presence and absence of
sodium ascorbate, except that at the end of the reac-
tion, the reaction became quantitative in the presence Discussion
of sodium ascorbate. In their study, Matyjasewski
et al. used hydrazine as an efficient oxidation inhibi- The CuAAC reaction has been shown during the last
tor.[14] Here, sodium ascorbate is not soluble in tolu- decade to be of considerable use to assemble chemi-
ene, but is also efficient as an oxidation inhibitor.
cals and materials,[6–15] but key issues remained con-
Given the ease of preparation of 1, it was probed as cerning pollution of product by copper residues and
a click catalyst for the synthesis of an 81-branch den- mechanistic aspects. This work contributes to the
drimer by 1!3 connectivity between a 27-branch group of known valuable Cu catalysts by the synthe-
azido-terminated dendrimer and a phenol dendron sis, characterization and study of both a new, very
that was propargylated at the focal point. This reac- convenient Cu(I) catalyst and of the first dendritic
tion had previously required a quantitative amount of Cu(I) catalysts. It also addresses the “greenness” of
CuSO4 in the presence of excess sodium ascorbate for the CuAAC process and the mechanistic problem.
completion, and lower amounts were not efficient. It
was believed that chelating coordination of Cu ions
by the dendritic triazole heterocycles forming tripods The Very Easily Synthesized, Efficient, Convenient,
inhibited their use as catalyst. Attempts to use the Soluble and Recyclable Catalyst 1
catalyst 4 under various conditions for this reaction
also failed, presumably because of steric effects of the The catalyst 1 is of the Cu(I)(polyamine) catalyst
alkyl branches of the tren ligand. Indeed, 6% of com- family including [Cu(I)(hexamethyltren)][Br] that has
plex 1 successfully catalyzed the quantitative synthesis been disclosed by the Matyajeswski group,[14] but the
of the 81-allyl dendrimer (Scheme 4).
very easily synthesized complex 1 is toluene soluble
unlike [Cu(I)(hexamethyltren)][Br], which allows its
easy separation from the triazole products by filtra-
tion. It is important to remove the copper catalyst
from the triazole product for both toxicity and recy-
cling reasons. Thus, it has been possible to show its
re-use. Although 1 is somewhat air sensitive, it has
Catalysis of the Click Reaction of Water-Insoluble
Substrates on Water by the Water-Soluble Cu(I)
Complex 5 without Cosolvent
The CuAAC reaction of water-insoluble substrates been demonstrated that it could be used here in very
was also catalyzed on water under air by 0.1% mol of low amounts such as 0.1 mol% vs. substrates and even
the water-soluble catalyst 5 at 228C (Table 5). Under recycled or recharged with substrates under nitrogen
these conditions, the selectivity was either total or ten times even in the absence of an oxidation inhibi-
very high. Again, the selectivity results of Table 1 can tor. In this way, turnover numbers of the order of 104
be improved by simply raising the amount of catalyst were obtained. For a more comfortable use, it is also
used as in Table 1 in toluene. Under the reaction con- possible to add sodium ascorbate as the oxidation in-
ditions, the catalyst 5 is not air sensitive. Note that hibitor. The latter does not change the mechanism as
the non-catalyzed reaction is also quite efficient on shown by superposition of the kinetic diagrams, but
water with several substrates. In some cases such as the reaction yields can be improved if the amount of
the reaction between 1-adamantyl azide and ethoxy- catalyst is very low, and maximum selectivity is then
carbonylacetylene, the non-catalyzed reaction pro- guaranteed. Another caution in using catalytic
ceeds equally well on water and in the absence of amounts lower than 0.1 mol% amount vs. substrate
water, whereas the non-catalyzed reaction between concerns the selectivity that decreases at too low cata-
benzyl azide and phenylacetylene proceeds much lyst concentrations because of the mixture between
more easily on water than in the absence of water.
the catalyzed and non-catalyzed reactions for which
The catalyst 5 was easily separated by filtration of data have also been searched here and reported in
the water-insoluble product and re-used twice in 0.1% the tables for comparisons.
molar amount vs. substrates providing 100% yield and
selectivity for the reaction between benzyl azide and catalyst CuSO4 +sodium ascorbate,[6] the catalyst 1
phenylacetylene. not only provides ligand acceleration of the reaction,
Compared to the very practical Fokin–Sharpless
Attempts to carry out reactions in a 1/1 THF/H2O but much more importantly, it protect the Cu(I) cata-
mixture led to results that were worse than on water lyst against coordination by the 1,2,3-triazole hetero-
alone. For comparison, the CuAAC reaction catalyzed cycles that are formed in these click reactions. In
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Scheme 4. Synthesis of the 81-branch dendrimer 12 using catalytic amounts of 1.
simple cases, this coordination does not inhibit cataly- comes crucial, however, to such an extent that the use
sis, because it is reversible, that is, weak enough. In of the CuSO4/sodium ascorbate catalyst no longer
some nanomaterial click syntheses, the problem be- works in catalytic amounts but must be used stoichio-
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
Table 5. CuAAC reactions catalyzed by 5 in water without co-solvent.
No. R1[a] R2[a]
T [8C] t [h] Yields[b] with cat. 5, in
Yields[b] without catalyst, on
water
Yields[b] without catalyst,
neat
water
M
S
T
M
S
T
M
S
T
1
2
4
5
6
7
8
9
Bn Ph
Bn Ph
22
60
22
60
22
22
24
24
24
24
48
72
24
24
72
24
100
100
99
91
78
99
97
96
100
96
0
0
1
0
0
0
3
0
0
2
100
100
100
91
78
99
100
96
100
98
1
82
2
25
22
0
0
34
8
2
16
0
1
1
0
0
0
0
3
98
2
26
23
0
0
34
8
0.5
6.8
1.7
37
10
0
0
4
0
66
0.6
3.2
0
2
0
0
0
0
0
1.1
10
1.7
39
10
0
0
4
0
72
Bn n-Bu
Bn SiMe3
Bn SiMe3
Bn Fc
R3 CH2OH 22
R3 R4
22
22
10 R3 R5
11 Ad CO2Et 22
56
6
62
6
[a]
R1 and R2 are defined in the CuAAC equation of Table 1. 1 mmol of each reactant and 0.1% mmol of the catalyst 5 were
used for the click reaction in 1 mL H2O.
Determined by GC, two runs, ꢁ3%. Isolated yields are 1% to 10% lower. The turnover numbers (TONs) are ten times
larger than the yields%. M=major isomer, S=minor 1,5-triazole isomer, T=total product. Fc=ferrocenyl. R3 =m-
MeBn; R4 =p-CH3OC6H4; R5 =p-CHOC6H4.
[b]
metrically. This is what we have experimented in the Metalloenzyme Mimic by Cu(I)-Centered
recent past with both click dendrimer synthesis[18] and Metallodendrimers: The Positive Dendritic Effect
gold nanoparticle click fonctionalization.[19] The prob-
lem is related to the fact that Cu(I) is only weakly li- It is remarkable that the kinetics is faster for some
ganded by the solvent and/or ascorbate. These very substrates with the bulky dendritic catalysts 2 and 3
weak ligands are displaced by stronger chelating tri- than with the related non-dendritic parent analogue 1
ACHTUNGTRENNUNGazole ligands that bind the copper ions in chelating as shown here upon comparing the reaction rates of
dendritic branches more strongly than monodentate the Cu(I)ACTHNUTRGNE(NUG tren) catalysts 1–4. This property is reminis-
triazoles.[18] Similar effects and/or aggregation with cent of metalloenzyme caytalysis.[4] Supramolecular
the metal core in gold nanoparticle syntheses also metal-substrate arrangements and forces are responsi-
provoke the need of stoichiometric amounts of ble for this trend. It is probable that orientation of
CuSO4 +sodium ascorbate “catalyst”.[19] In both substrates in key rate-limiting (transition) states are
areas, medicinal applications of the click reaction rendered more favorable at the metallodendritic
have enormous potential, and thus the use of stoichio- center due to conformational and steric effects within
metric amounts of Cu “catalyst” is prohibited.
Catalyst 1 is possibly not as efficient as the rarely been disclosed in metallodendrimer chemis-
Cu(I)
[tris(triazolylmethyl)amine] and related catalysts try,[22] because the dendritic steric bulk usually consid-
the dendrimer interior.[16] This property has very
ACHTUNGTRENNUNG
of the Scriptꢂs group,[12,13,17], but its efficiency is excel- erably slows down the reaction kinetics, and dendri-
lent as exemplified by its use in low amount (0.1%) in mer chemists prefer to load their catalysts at the den-
standard reactions and successful use in the synthesis drimer periphery for dendritic recycling.[16] Here, not
of an 81-branch dendrimer whereas the use of only is the kinetics faster with the G1 dendrimer 2
CuSO4 +sodium ascorbate was previously required in than with the parent catalyst 1, but also the G2 den-
stoichiometric amounts. Thus 1 is far from unique, but drimer 3 provides a faster reaction than the G1 den-
its solubility, recyclability, efficiency and simplicity of drimer 2, that is, the dendritic effect is continuously
synthesis are remarkable, and we have been able to positive. In addition, the dendritic Cu(I) catalysts 2
show here its efficient specific use. Finally, an even and 3 are much more air stable than 1. Obviously,
simpler use involves the addition of CuBr and hexa- only a few substrates can serendipitously be observed
benzyltren in catalytic amounts providing a catalytic to show faster kinetics in this catalytic metalloden-
system in toluene that is very efficient. The latter al- drimer series compared to the parent catalyst 1, be-
ternative is all the more useful as there is no need to cause steric effects of larger substrates facing dendrit-
store the catalyst away from air, because neither ic bulk around the Cu(I) center rapidly dominate the
CuBr nor the ligand is air sensitive.
reaction kinetics. An extreme case is the click reac-
tion in the dendritic branches for the construction of
the 81-branched dendrimer that can only be catalyzed
by a small non-dendritic catalyst such as 1, whereas
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larger catalysts of the same Cu(I)ACTHNUTRGNE(NUG tren) family such as and in-depth kinetic studies by the groups of Finn and
4 have failed to catalyze this latter reaction.
of Fokin have shown the mechanistic complexity of
this reaction, and in particular it has been suggested
that several mechanisms with close energies of transi-
tion states could be involved.[13] In the present study,
the polydentate dendritic polyamine ligands isolate
the Cu(I) center, and the large bulk around the metal
Catalysis in Water by the Recyclable Water-Soluble,
Air-Stable Dendritic Catalyst 5
CuAAC catalysis in water without co-solvent of the center inhibits the approach of a second copper atom.
water-soluble air-stable dendritic catalyst in Consequently, there is no room here for an alkynyl-
5
0.1 mol% amount vs. substrate can be followed by bridged intermediate or transition state. One might
easy recovery of the catalyst by filtration of the water argue that a very small amount of copper could
suspension of the product, then re-use of the catalyst. escape from the coordination sphere of the ligand,
Thus, only very minute amounts of a robust Cu com- but CuBr is not soluble, and is a very poor catalyst
plex are engaged in the reaction, and this catalyst is under the reaction conditions, as we have checked.
easily removed and re-used. The stability in air, use in There is also obviously too much bulk to allow two
water only at 228C (ambient, biocompatible condi- dendritic Cu(I)tren complexes to approach each other
tions), recyclability, and very small quantity of copper and share a bridging alkynyl and a polyamine ligand
used and recovered are fine advantages in the context such as in the key species suggested by Fokin and
of green chemistry.
Finn.[13] Another argument is the positive dendritic
Reactions “on” water are well documented in the effect on the catalysis kinetics, the rate acceleration
literature, and a recent excellent review is available.[23] by the tren ligand being all the greater, as the dendri-
In the present case, the dendrimer works in the fash- mer is larger, whereas the approach of any other Cu
ion of a molecular micelle, a concept developed by species is rendered more difficult because of the in-
Newkome.[21a,24] The hydrophobic substrates are stabi- creased steric effect of the dendrimer. Thus, it appears
lized inside the hydrophobic dendrimer interior where that no bimetallic catalyst, but only a monometallic
they can meet at the dendritic Cu(I) center for cata- Cu(I)
ACHTUNGTRENNUNG
lytic formation of the products. There is an equilibri- series of Cu(I)
AHCTUNGTRENNUNG
um between the insoluble substrates and the dendri- This view is not conflicting with the mechanism pro-
mer-encapsulated substrates, and this equilibrium is posed for the Cu(I)-TBTA catalysis in non-dendritic
displaced by the “click” reaction towards the product complexes, because it is probable that the nuclearity
formation. Such an example has recently been dem- of the CuAAC catalysis depends on the structure of
onstrated for olefin metathesis whereby the molecular the catalyst and reaction conditions. Indeed, an intri-
catalyst, that is not attached to the dendrimer, is also guing point in this respect is the different kinetics ob-
hydrophobic.[25] In a different approach, catalysis in served for CuBr+hexabenzyltren compared to the
water of the CuAAC reaction between the water- preformed catalyst 1. The faster rate observed with
soluble substrates azidopropanol and propargyl alco- CuBr+hexabenzyltren could be due to the occur-
hol using 8% Cu per substrates has very recently rence of the Fokin–Finn bimetallic mechanism, be-
been shown to proceed with >95% conversion in 1– cause in the presence of both tren and the alkyne, the
3 h using Cu(I)/Cu(0) loaded in polyamidoamine competition of complexation could lead to direct for-
(PAMAM) dendrimers PAMAM-OH and PAMAM- mation of the Cu(I)-acetylide oligomers before com-
NH2 with Cu:ligand ratios of 1:1 and 30:1, respective- plexation of tren, so that the species Cu(I)2-s,m-
ly.[26] More generally, several Cu catalysts have recent- alkynyl
ACTHNUGRTENUNG(tren) of Figure 3, analogous to the proposi-
ly been reported in the context of “green chemis- tion of Finn and Fokin, could be the key active spe-
try”.[27]
cies with bimetallic tren coordination. This species
has been proposed by Finn and Fokin to better acti-
Efficient Metallodendritic Catalysts: Evidence for a
Monometallic CuAAC Mechanism
It has been well emphasized that oligomeric Cu-alk-
ACHTUNGTRENNUNGynyl species in fast interconversion between frag-
ments of various nuclearities are involved in the
CuAAC catalysis by the very efficient Cu(I) catalysts
containing a ligand of the tris(triazolylmethyl)amine
(TBTA) family.[13] Among these species, alkynyl-
Figure 3. Key catalytically active bimetallic species proposed
by Finn and Fokin[13] for the CuAAC reaction (extended
bridged bisACHTUNGTRENNUNG(copper) species were believed to be key
species undergoing the attack by the azide. Detailed here to tren).
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
Scheme 5. Proposed mechanisms for the CuAAC reaction catalyzed by the Cu(I)ACTHNUTRGENUG(N tren) catalysts 1–5. A: Azide attack on the
a alkynyl carbon. B: Azide attack on the metal (Fokin–Finn-type mechanism adapted to tren).[13]
vate the alkyne towards azide attack, and the faster metallic activation that is inhibited in the cases of the
reaction observed under the present CuBr+ligand pre-formed Cu(I)-tren catalysts.
conditions could be taken into account by such a bi-
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The [Cu(I)
G
16-electron or an 18-electron configuration depending
on whether three or four tren nitrogen atoms are co- The new CuAAC catalyst [Cu(hexabenzyl)tren[[Br]
ordinated to the Cu(I) center, that is, there could be a (1) is very easy to synthesize, toluene soluble, effi-
doubt concerning the coordination of the apical nitro- cient, easy to separate from products and recyclable
gen. However, Matyajeswskiꢂs group has shown that even if it is used in only 0.1 mol% amount vs. sub-
the tridentate nitrogen ligands provided a significantly strates. TONs of the order of 104 can be reached upon
faster kinetics than the tetradentate ligands such as recharching substrates. Below this molar amount per
tren. Since it is well recognized that the first step is p substrate, some substrates lead to traces of the minor
coordination of the alkyne onto Cu(I),[7] this step 1,5-triazole isomer due to a small amount of non-cata-
must involve a rate-limiting ligand substitution of the lyzed reaction. The presence of sodium ascorbate
apical nitrogen ligand of tren by the p-alkyne ligand, eventually optimizes the CuAAC reaction by prevent-
because otherwise an improbable high-energy 20-elec- ing aerobic oxidation. The catalyst 1 is impressively
tron configuration would need to be reached by convenient for the click synthesis of nanomaterials
Cu(I). The acidity of the p-alkyne is enhanced by the such as large dendrimers that previously required the
coordination to Cu(I), and the free apical nitrogen use of stoichiometric amount of CuSO4 and sodium
then becomes a good base for deprotonation of the p- ascorbate or could not be synthesized using large mo-
alkyne ligand to give the neutral 18-electron s-alkyn- lecular catalysts such as [Cu
ACTHUGNERTNN(NUG C18H37)6tren]Br (4).
yl-Cu(I) intermediate. DFT calculations had shown Another very convenient alternative is the use of
that the acidity of the alkyne was, as expected, consid- CuBr+(hexabenzyl)tren in toluene that, remarkably,
erably enhanced (lowering of the pKa by 9.8 units) by proceeds with faster kinetics than the preformed cata-
p-coordination to the cationic Cu(I) center.[28] In such lyst 1 (100% yield in 10 min with 0.1 equiv. catalyst
s-alkynyl complexes, the s-alkynyl polarization brings for the reaction of phenylacetylene with benzyl
a small fractional positive charge on the a carbon azide), probably due to a bimetallic mechanism relat-
atom, and a LUMO of this ligand is polarized on the ed to that proposed by Finn and Fokin.[13]
a carbon atom. Therefore, this situation is favorable
The catalyst 1 serves as a model for the construc-
for a direct azide attack onto this a carbon atom tion of the robust Cu(I)-centered dendrimers 2 and 3
(Scheme 5, A). Upon approaching the a carbon atom in which aerobic Cu(I) oxidation to m-oxo-bridged di-
of the alkynyl ligand, the negatively charged nitrogen copper species is sterically prevented. These metallo-
atom of the azide can favorably polarize the p elec- dendrimers catalyze the CuAAC reaction between
ꢀ
tronic cloud of the triple bound before N C bond for- azidomethylbenzene and phenylacetylene more rapid-
mation. It has been proposed that the azide attacks a ly than the non-dendritic complexes 1 or 4 with a pos-
Cu(I) center before its migration to the a carbon itive dendritic effect recalling enzymatic catalysis. The
atom, and this possibility is also alternatively ade- water-soluble Cu(I) dendritic complex 5 catalyzes the
quate (Scheme 5, B).[7]
click reaction of water-insoluble substrates at 0.1
It does not appear as mechanistically indispensable, mol% per mol substrate at 228C on water in air, and
however, partly because the azide would then have to is recyclable with quantitative yield even at such a
displace another nitrogen ligand in the 18-electron low catalyst concentration. The robustness of these
Cu(I)-s-alkynyl species (which is also eventually fea- Cu(I) catalysts compared to the very poor catalytic
sible) and partly because nucleophilic attacks on the activity of CuBr under the same conditions together
a carbon atoms of ligands are widespread in organo- with the above data show that a monometallic mecha-
metallic chemistry.[29,30] This polarization of the s-al- nism proceeds in the case of the dendritic or star
kynyl ligand and disymmetrization of the alkyne ex- Cu(I)
plains the regioselectivity for the formation of the 1,4-
triazole isomer. A bimetallic mechanism proposed
ACHTUNGTREN(NUNG tren) catalysts 2–5.
earlier in which the alkynyl ligand binds one Cu(I) Experimental Section
center and the azide the other one[31] cannot occur
either here at the bulky Cu(I)-center of metalloden- General data
drimers for the reason stated above. The remaining
See the Supporting Information.
known steps of the mechanism[13] are metal-heterocy-
cle formation followed by protonation of the Cu(I)
Synthesis of the Ligand (Benzyl)6tren
center by the nearby ammonium center of the salt
[trenH][Br] to give the Cu(III) cationic copper-hy-
dride intermediate and reductive elimination of the
AHCTUNGTRENNUNG
A suspension of bromomethylbenzene (1.5 g, 8.8 mmol),
tris(2-aminoethyl)amine (0.18 g, 1.3 mmol) and K2CO3
(1.9 g, 13.8 mmol) was refluxed in CH3CN under N2. After
48 h, the mixture was cooled in an ice bath, the solid residue
was washed with acetonitrile, water, and MeOH and then
triazole from the cationic [Cu
cies (Scheme 5).
(III)(triazolyl)(H)]+ spe-
ACHTUNGTRENNUNG
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The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions
dissolved in hot toluene. The toluene phase was washed
with brine, dried over Na2SO4, the solvent was removed
under vacuum, and the resulting solid was precipitated in
methanol giving (benzyl)6tren as a light-yellow gel; yield:
(C*CH2CH2CH2), 14.7 (C*CH2CH2CH2), ꢀ4.5 [Si
ACHTUNGTRENNUNG(CH3)2];
anal. calcd. for C492H678O24N4Si18: C 78.45, H 9.01; found: C
76.44, H 9.11; DLS: r=4.1 nm (PDI=0.34).
1
0.84 g (97.7%). H NMR (CDCl3, 250 MHz): d=7.34 (30H,
Synthesis of the Ligand G’2
CH, arom.), 3.50 (12H, NCH2Cq), 2.46, (12H, NCH2CH2N);
13C NMR (CDCl3, 75 MHz): d=138.7 (NCH2Cq), 127.7,
127.0, 125.7 (CH arom.), 57.7 (NCH2Cq), 51.9
(NCH2CH2N*), 50.3 (NCH2CH2N*); anal. calcd. for
C48H54N4: C 83.92, H 7.92; found: C 83.64, H 7.96; MS
(MALDI-TOF): m/z=687.5, calcd. for C48H54N4: 686.2.
The dendron 8 (210 mg, 5ꢄ10ꢀ5 mol, 1 equiv.) and the den-
dron 7 (683 mg, 1.08ꢄ10ꢀ3 mol, 20 equiv.) were dissolved in
5 mL toluene, then the catalyst 1 (9 mg, 1.08ꢄ10ꢀ5 mol,
0.2 equiv., 1 mol%) was added. The light brown solution
was stirred for 24 h at 228C under nitrogen. After removing
toluene under vacuum, the mixture was washed several
times with dried diethyl ether to remove the excess of den-
dron 7, then precipitated in toluene giving the ligand G’2 as
a yellow-brown gel; yield: 0.63 g (51.6%). The infrared spec-
trum shows the disappearance of the band at 2098 cmꢀ1 that
is characteristic of the azide function and of the band at
Synthesis of the Ligand G1
A suspension of 14 (0.55 g, 1.34 mmol), tris(2-aminoethyl)-
ACHTUNGTRENNUNGamine (28 mg, 0.19 mmol) and K2CO3 (0.29 g, 2.1 mmol) was
refluxed in CH3CN under N2. After 48 h, the mixture was
cooled in an ice bath, the solid residue was washed with ace-
tonitrile, water, and MeOH and then dissolved in hot tolu-
ene. The toluene phase was washed with brine, dried over
Na2SO4, the solvent was removed under vacuum, and the re-
sulting solid was precipitated in methanol giving the ligand
1
2112 cmꢀ1 for the terminal alkyne group. H NMR (CDCl3,
300 MHz): d=7.42 (18H, CH of triazole), 7.35 (24H, CH of
intern. arom), 7.14, 6.9 (24H, CH of middle arom.), 6.57
(36H, CH of extern. arom.), 4.93 (12H, CH2O-arom), 4.63
(36H, triazole-CH2), 4.46 (36H, O-CH2-arom), 4.13 (144H,
arom-OCH2 and Si-CH2-N), 3.83–3.54 (552H, OCH2CH2O
and NCH2-arom), 3.35 (162H, OCH3), 2.52 (12H,
NCH2CH2N), 1.6 (36H, CH2CH2CH2Si), 1.06 (36H,
CH2CH2CH2Si), 0.59 (36H, CH2CH2CH2Si), 0.04 [108H,
1
G1 as a colorless solid; yield: 0.3 g (75%). H NMR (CDCl3,
250 MHz): d=7.42 (24H, CH, arom.), 7.32 and 7.02 (24H,
CH arom.), 5.64 (18H, CH2CH=CH2), 5.1 (48H, CH2CH=
CH2 and CH2O), 3.56 (12H, CH2Cq), 2.52, 2.43 (48H,
NCH2CH2N and CH2CH=CH2); 13C NMR (CDCl3,
75 MHz): d=156.9 (CqO), 139.7 (CqCH2O), 138.0 (CqC*),
135.8 (NCH2Cq), 134.7 (CH2CH=CH2), 129.0, 127.8 (CH
arom.), 117.7 (CH2CH=CH2), 114.3 (CH arom.), 69.9
(CH2O-Cq), 58.6 (NCH2Cq), 53.2 (NCH2CH2N*), 51.6
(NCH2CH2N*), 42.8 (CH2CH=CH2), 42.1 (benzylic quater-
nary C of the core); MS (MALDI-TOF): m/z=2129, calcd.
for C150H174O6N4: 2126; anal. calcd. for C150H174O6N4: C
84.67, H 8.18; found: C 84.24, H 8.14; DOSY: diffusion co-
efficient D=KBT/6phrH, D=1.96 (ꢁ0.1)ꢄ10ꢀ10 m2/s, rH =
1.92 (ꢁ0.1) nm.
SiACTHNUTRGNEUNG
(CH3)2]; 13C NMR (CDCl3, 75 MHz): d=156.4 (CqO
middle), 152.5 (CqO extern.), 144.6 (Cq of triazole), 139.3
(CqCH2O intern and Cq of middle arom), 137.7 (OCH2Cq
extern), 135.6 (NCH2Cq), 133.3 (OCH2Cq extern), 128.9,
127.3 (CH of intern. arom), 127.6, 114 (CH middle arom),
123.4 (CH of triazole), 107.2 (CH of arom extern), 71.8–69.6
(OCH2CH2O), 68.7 (CH2O-arom), 63.5 (triazole-CH2O),
58.9 (NCH2Cq and OCH3), 53.6 (NCH2CH2N), 43
(CH2CH2CH2Si), 41.6 (CqCH2CH2CH2Si), 40.9 (SiCH2N),
17.3 (CH2CH2CH2Si), 14.7 (CH2CH2CH2Si), ꢀ4.03
[SiACHTUNGTRENUNG(CH3)2]; anal. calcd. for C762H1272O240N58Si18: C 58.7, H
8.22; found: C 58.19, H 7.87.
Synthesis of the Ligand G2
General Procedure for the Synthesis of the
A
suspension of 16 (see the Supporting Information)
Cu(I)ACHTNUGRTNEUNG
(tren) Catalysts[15]
(0.58 g, 0.44 mmol), tris(2-aminoethyl)amine (9.2 mg,
0.063 mmol) and K2CO3 (96 mg, 0.70 mmol) was refluxed in
CH3CN under N2. After 48 h, the mixture was cooled in an
ice bath, the solid residue was washed with acetonitrile,
water, and MeOH and then dissolved in hot toluene. The
toluene phase was washed with brine, dried over Na2SO4,
the solvent was removed under vacuum, and the resulting
solid was precipitated in methanol giving the ligand G2 as a
colorless solid; yield: 0.27 g (57.4%). 1H NMR (CDCl3,
250 MHz): d=7.39, 7.23, 6.92 (120H, CH, arom.), 5.57
(54H, CH2CH=CH2), 5.03 (120H, CH2CH=CH2 and Cq-
The complex CuBr/ligand tris(2-aminoethyl)amine (tren)
was prepared by using a slight excess (1.1/1) of CuBr and
the tren ligand in freshly distilled 1,4-dioxane at 608C over-
night. Then, the solution was filtered under nitrogen to
remove the excess of CuBr. After removing the solvent
under vacuum, the product (off-white gel) was kept under
nitrogen.
Catalyst 1: 1H NMR (CDCl3, 250 MHz): d=7.31 (30H,
CH, arom.), 3.49 (12H, NCH2Cq), 2.47, 2.23 (12H,
NCH2CH2N); 13C NMR (CDCl3, 75 MHz): d=137.9
(NCH2Cq), 127.7, 127.0, 125.7 (CH arom.), 59.5 (NCH2Cq),
52.8 (NCH2CH2N*), 49.4 (NCH2CH2N*); anal. calcd. for
C48H54N4CuBr: C 69.57, H 6.52; found: C 68.71, H 6.52; MS
(MALDI TOF): m/z=830, calcd. for C48H54N4CuBr: 829.
The cyclic voltammogram (see the Supporting Information)
shows an electrochemically irreversible oxidation wave at
CH2O), 3.53 (48H, NCH2Cq and SiACHTUNGTRENUNG(CH3)2CH2O), 2.45,
(120H, NCH2CH2N and CH2CH=CH2), 1.68 (36H,
C*CH2CH2CH2), 1.19 (36H, C*CH2CH2CH2), 0.63 (36H,
C*CH2CH2CH2), 0.08 [108H, Si
75 MHz): d=159.5 [Si(CH3)2CH2O-Cq],
(CqCH2OCq), 137.3 (CqCH2O, CqC*), 134.8 (NCH2Cq,
CH2CH=CH2), 127.5 (CH arom. of Cq), 117.5 (CH2CH= Epa =1.10 V vs. [Co
CH2), 113.6 (CH arom. of Cq), 69.9 (Cq-CH2O-Cq), 60.2
[PF6][32] as the internal reference and [n-Bu4N]
[NCH2Cq and Si(CH3)2CH2O], 53.2 (NCH2CH2N*), 51.8 the supporting electrolyte in CH2Cl2 on Pt. The Epa value is
(NCH2CH2N*), 43.2 (C*CH2CH2CH2), 42.7 (CH2CH=CH2), 0.30 V vs. [Fe DEp=0.40 V, partial chemical
(C5Me5)2]+/0 [32]
42.1 (benzylic quaternary of the core), 17.8
reversibility (ic/ia =0.5 at the scan rate of 0.1 V sꢀ1). For in-
(CH3)2]; 13C NMR (CDCl3,
ACHTUNGTRENNUNG
A
156.5
A
ACHTUNGTRENNUNG(C5H5)2]
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
,
Adv. Synth. Catal. 2011, 353, 3434 – 3450
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3447

Liyuan Liang et al.
FULL PAPERS
terconversion of the metallocene reference potentials, see
ref.[32] UV-vis.: c=0.0004 mol/L in CH2Cl2, l=316 nm, e=
2690 L. molꢀ1 cmꢀ1 for cat.1 (see Figure 2 in the Supporting
Information).
freshly distilled toluene or pentane (1 mL) (or neat) or
water at 228C or at 608C under pressure of nitrogen in the
sealed Schlenk flask. The reaction was monitored by GC
(see Table 1).
Catalyst 2: 1H NMR (CDCl3, 250 MHz): d=7.34 (24H,
CH, armo.), 7.21 and 6.94 (24H, CH arom.), 5.57 (18H,
CH2CH=CH2), 5.0 (48H, CH2CH=CH2 and CH2O), 3.49
(12H, CH2Cq), 2.44, 2.42 (48H, NCH2CH2N and CH2CH=
CH2); 13C NMR (CDCl3, 75 MHz): d=155.7 (CqO), 138.8
(CqCH2O), 136.9 (CqC*), 135.4 (NCH2Cq), 133.2 (CH2CH=
CH2), 128.7, 126.8 (CH arom. of Cq), 116.2 (CH2CH=CH2),
113.1 (CH arom. of Cq), 68.5 (CH2O-Cq), 58.1 (NCH2Cq),
52.1 (NCH2CH2N*), 51.1 (NCH2CH2N*), 41.7 (CH2CH=
CH2), 41.0 (benzylic quaternary of the core); UV-vis.: l=
Procedure for Recycling the Cu(I) Catalysts
In a 10-mL Schlenk flask fitted with a stirring bar, the cata-
lyst [CuACHTNUTGRNEUNG(C24H27O)6tren]Br (2), [Cu(C81H111O4)6tren]Br (3),
or [Cu(C126H210O40N9Si3)6tren]Br (5) (0.1 mmol% equiv.),
the azide (1 mmol) and the alkyne (1.05 mmol) were stirred
in freshly distilled toluene for 2 and 3 (1 mL) or H2O for 5
at 228C, and the reaction was monitored by GC. After each
24 h, the reaction mixture was cooled at ꢀ188C for 30 min
in order to complete precipitation of the product, then fil-
tered and washed three times in order to recyle the catalyst,
then the catalyst solution was concentrated to l mL, which
allowed us to reload the substrates for the next reaction (see
Table 3).
262 nm,
e=2003 Lmolꢀ1 cmꢀ1
;
anal.
calcd.
for
C150H174O6N4CuBr: C 79.37, H 7.67; found: C 78.53, H 7.59;
DOSY: D=KBT/6phrH, D=5.81 (ꢁ0.1)ꢄ10ꢀ10 m2/s, rH =
0.65 (ꢁ0.01) nm.
Catalyst 3: 1H NMR (CDCl3, 250 MHz): d=7.41, 7.20,
6.92 (120H, CH, armo.), 5.57 (54H, CH2CH=CH2), 5.0
(120H, CH2CH=CH2 and Cq-CH2O), 3.54 (48H, NCH2Cq
and Si
CH2),
ACHTUNGTRENNUNG
Acknowledgements
C*CH2CH2CH2), 0.64 (36H, C*CH2CH2CH2), 0.09 [108H,
Si(CH3)2]; (CDCl3, 75 MHz): d=159.3
13C NMR
[Si(CH3)2CH2O-Cq], 156.4 (CqCH2OCq), 137.1 (CqCH2O,
ACHTUNGTRENNUNG
Helpful discussions with Dr. J.-M. Vincent (Talence) and fi-
nancial support from the CNRS, the Universitꢀ Bordeaux 1,
and the ANR (07-CP2D-05-01) are gratefully acknowledged.
ACHTUNGTRENNUNG
CqC*), 134.5 (NCH2Cq, CH2CH=CH2), 127.3 (CH arom. of
Cq), 117.2 (CH2CH=CH2), 113.5 (CH arom. of Cq), 60.0
[NCH2Cq and Si
ACHTUNGTRENNUNG(CH3)2CH2O], 43.1 (C*CH2CH2CH2), 42.6
(CH2CH=CH2), 41.9 (benzylic quaternary of the core), 17.6
(C*CH2CH2CH2), 14.5 (C*CH2CH2CH2), ꢀ4.6 [Si
ACHTUGNRTNE(NUNG CH3)2];
UV-vis.: l=275 nm, e=2648 Lmolꢀ1 cmꢀ1; anal. calcd. for
C492H678O24N4Si18CuBr: C 76.99, H 8.84; found: C 76.10, H
8.92.
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