Highly efficient ambient-temperature copper-catalyzed atom-transfer radical addition (ATRA) in the presence of free-radical initiator (V-70) as a reducing agent

Article abstract of DOI:10.1002/chem.200802048

Highly efficient, ambient-temperature, copper-catalyzed Atom Transfer Radical Addition (ATRA) of polyhalogenated compounds to alkenes in the presence of free radical initiator 2,2' -azobis (4-methoxy-2,4-dimethyl valeronitrile)(V-70)as a reducing agent was reported. The discrepancies between the alkene conversion and percent yield were mostly due to competing free-radical polymerization. ATRA of polyhalogenated compounds to monomers that are highly active in free-radical polymerization was not successful at 60 ^° C when AIBN was used as radical initiator. The V-70 was proved to be very effective reducing agent, enabling selective formation of the monoadduct with α -olefins and highly active monomers such as methyl acrylate, methyl methacrylate, and vinyl acetate. The methodology for catalyst regeneration in copper-mediated ATRA in the presence of V-70 as a reducing agent also worked very well in the addition of CCl₄ and CBr₄ to highly active vinyl acetate.

Full text of DOI:10.1002/chem.200802048

DOI: 10.1002/chem.200802048
Highly Efficient Ambient-Temperature Copper-Catalyzed Atom-Transfer
Radical Addition (ATRA) in the Presence of Free-Radical Initiator (V-70) as
a Reducing Agent
Tomislav Pintauer,* William T. Eckenhoff, Carolynne Ricardo, Marielle N. C. Balili,
Ashley B. Biernesser, Sean J. Noonan, and Matthew J. W. Taylor[a]
The addition of halogenated compounds to carbon–
carbon double (or triple) bonds through a radical process is
one of the fundamental reactions in organic chemistry.[1] It
was first reported in the mid 1940s in a reaction in which
halogenated alkenes were directly added to olefinic bonds
in the presence of free-radical initiators or light.[2] Today,
this reaction is known as the Kharasch addition or atom-
transfer radical addition (ATRA), and it is typically cata-
lyzed by transition-metal complexes of Ru, Fe, Ni, and
Cu.[3–6] Transition-metal-catalyzed ATRA, despite being dis-
covered nearly 40 years before the widely used tin-mediated
radical addition to olefins[7] and iodine atom-transfer radical
addition,[8] is still not fully utilized as a technique in organic
synthesis. Until recently, the principal reason for small par-
ticipation of ATRA in complex molecule and natural prod-
uct syntheses remained the large amount of transition metal
needed to achieve high selectivity towards the desired target
compound (typically 5–30 mol% relative to alkene).[3,9] This
obstacle caused serious problems in product separation and
catalyst regeneration, making the process environmentally
unfriendly and expensive.
oxidation state) in the presence of reducing agents, such as
phenols, glucose, ascorbic acid, hydrazine, tin(II) 2-ethylhex-
anoate magnesium, and free-radical initiators (Scheme 1).[3]
Scheme 1. Proposed mechanism for copper(I) regeneration in the pres-
ence of reducing agent (AIBN) during ATRA process.
Originally, the solution to this problem has been found
for copper-catalyzed atom-transfer radical polymerization
(ATRP),[3,10,11] and was subsequently applied first to rutheni-
um-[12] and then copper-catalyzed[13,14] ATRA reactions. In
all of these processes, the activator (transition-metal com-
plex in the lower oxidation state) is continuously regenerat-
ed from deactivator (transition-metal complex in the higher
When applied to ATRA of CCl4 to alkenes catalyzed by
[RuIIICp*Cl
2A
(Cp*=pentamethylcyclopentadiene)
complex in the presence of AIBN (azobisisobutyronitrile),
turnover numbers (TONs) as high as 44500 were ob-
tained.[12] Even more impressive TONs were achieved with
CBr4 and [CuII
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Prof. T. Pintauer, W. T. Eckenhoff, C. Ricardo, M. N. C. Balili,
A. B. Biernesser, S. J. Noonan, M. J. W. Taylor
Department of Chemistry and Biochemistry
Duquesne University, 600 Forbes Avenue
308 Mellon Hall, Pittsburgh, PA 15282 (USA)
Fax : (+1)412-396-5683
ATRA reactions in the presence of as little as 5 ppm of
copper.[13] Since the seminal reports by our research
group[14] as well as Severinꢀs,[12] this method of catalyst re-
generation in ATRA has attracted considerable academic
interest,[15–22] and was even successfully applied to intramo-
lecular ATRA or atom-transfer radical cyclization (ATRC)
reactions.[21–23]
E-mail: pintauert@duq.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802048.
38
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Chem. Eur. J. 2009, 15, 38 – 41

COMMUNICATION
Table 1. Ambient-temperature Kharasch addition of polyhalogenated
compounds to alkenes in the presence of V-70.
In our initial studies, AIBN was successfully utilized as a
reducing agent in copper-catalyzed ATRA of polyhalogenat-
ed compounds to alkenes at 608C.[13,14] Excellent results
were obtained in the case of simple a-olefins (1-hexene, 1-
decene, and 1-octene), as well as methyl acrylate and sty-
rene. However, this method of catalyst regeneration was not
very successful for monomers with high propagation rate
constants, such as methyl methacrylate (kp,60 =6.3ꢂ
102 mÀ1 sÀ1), vinyl acetate (kp,60 =2.3ꢂ103 mÀ1 sÀ1), and acrylo-
nitrile (kp,60 =1.9ꢂ103 mÀ1 sÀ1).[24] ATRA of these monomers
in the presence of AIBN at 608C yielded significant
amounts of polymers/telomers unless high copper loadings
and/or large excess of alkyl halide (4 equiv relative to
alkene) were used. The principal reason for the difficulty in
controlling the formation of single addition adduct was not
inefficient catalyst regeneration or further activation of the
monoadduct, but rather competing polymerization initiated
by the presence of AIBN (Scheme 1). The potential solution
to this problem is to utilize redox-reducing agents that do
not generate free radicals, such as magnesium.[21] However,
the presence of magnesium as a reducing agent is less de-
sired, because it increases the total metal concentration in
the system. An alternative solution is to utilize low-tempera-
ture free-radical initiators that could be used at ambient
temperatures and be easily removed from reaction mixtures
together with radical decomposition products. At ambient
temperatures, free-radical polymerization of highly active
Entry[a]
Alkene
RX
% Conv.
% Yield[b]
1
2
3
4
1-decene
CCl4
CHCl3
CBr4
5
3
55
3
0
0
53
0
CHBr3
5
6
7
8
1-octene
CCl4
CHCl3
CBr4
8
1
57
5
0
0
56
0
CHBr3
9
10
11
12
1-hexene
CCl4
CHCl3
CBr4
4
3
66
4
0
0
64
0
CHBr3
13
14
15
16
styrene
CCl4
CHCl3
CBr4
18
26
32
37
1
0
29
0
CHBr3
17
18
19
20
methyl acrylate
methyl methacrylate
vinyl acetate
CCl4
CHCl3
CBr4
88
83
96
51
0
0
38
37
CHBr3
21
22
23
24
CCl4
CHCl3
CBr4
86
83
91
96
0
0
8
CHBr3
14
monomers (3.0ꢂ102 sÀ1 <k
result of decrease in propagation rate constants (kp,25
(MMA)=1.9ꢂ102 mÀ1 sÀ1, kp,25(VA)=1.0ꢂ103 mÀ1 sÀ1 and
kp,25(AN)=9.3ꢂ102 mÀ1 sÀ1))[24] is expected to compete with a
d,2A
pA
a
25
26
27
28
CCl4
CHCl3
CBr4
18
11
30
6
16
0
27
0
-
ACHTUNGTRENNUNG
CHBr3
CHTUNGTRENNUNG
halide transfer (1.8ꢂ103 sÀ1 <k [CuIILmX2]<1.8ꢂ105 sÀ1) to
[a] All reactions were performed in CH3CN at 22Æ28C for 24 h with
[RX]0:[alkene]0:[V-70]0 =1:1:0.05, except reactions for entries 1–4 which
a much lesser extent.[25] Consequently, provided efficient re-
generation of the copper(I) complex, substantially higher
yields of the desired monoadduct could be obtained.
A
ACHTUNGTRENNUNG
were performed in 1,2-dichloroethane. [b] Yield is based on the forma-
tion of monoadduct and was determined by 1H NMR spectroscopy using
anisole (styrene) or 1,4-dimethoxybenzene (all other alkenes) as internal
standards.
In this article, we report on highly efficient, ambient-tem-
perature, copper-catalyzed ATRA of polyhalogenated com-
pounds to alkenes in the presence of free radical initiator
2,2’-azobis(4-methoxy-2,4-dimethyl valeronitrile) (V-70) as a
reducing agent.
between the alkene conversion and percent yield were
mostly due to competing free-radical polymerization.
The addition of polyhalogenated compounds (in particular
CBr4 and CCl4) to alkenes could proceed only in the pres-
ence of free-radical initiator, because of their known ability
to function as very efficient chain-transfer agents.[26,27] As in-
dicated in Table 1 (entries 3, 7, and 11), ambient-tempera-
ture, V-70-initiated Kharasch addition reactions in the pres-
ence of one equivalent of alkyl halide proceeded with rea-
sonably high yields only in the case of CBr4 and simple a-
olefins. However, the obtained yields of the monoadduct
(53–64%) were significantly lower than the yields obtained
at 608C in the presence of AIBN (96–100%).[13] Further-
more, the formation of monoadduct was observed in the V-
70-initiated free-radical addition of CBr4 to styrene
(entry 15), methyl acrylate (entry 19), and vinyl acetate
(entry 27) and CHBr3 to methyl acrylate (entry 20) and
methyl methacrylate (entry 24), albeit with much smaller
yields. For these highly active monomers, the discrepancies
ACTHNGUTERNNUG
When [CuII(tpma)X][X] (X=ClÀ (for RCl) or BrÀ (for
RBr)) was added to the reaction mixture at ambient temper-
ature, truly remarkable results were obtained (Table 2). For
ATRA of CCl4 to a-olefins (1-decene, 1-octene, and 1-
hexene) using stoichiometric amounts of both reagents, ex-
cellent yields of the monoadduct were obtained with CuII to
alkene ratio of 1:1000 (entries 1, 8, and 15). Further de-
crease in catalyst loading to 1:2000 (0.05 mol%) still result-
ed in high conversions and excellent yields of the monoad-
duct. Even more impressive results were obtained in ATRA
of CBr4 to 1-decene (entries 4–6), 1-octene (entries 11–13),
and 1-hexene (entries 18–20) using concentrations of copper
as low as 0.002 mol% (20 ppm relative to alkene)
(Figure 1). On the other hand, CHCl3 and CHBr3 were
found to be quite inactive in ATRA reactions with a-olefins
at ambient temperatures, at catalyst loadings as high as
10 mol%.
Chem. Eur. J. 2009, 15, 38 – 41
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www.chemeurj.org
39

T. Pintauer et al.
Table 2. Ambient-temperature ATRA of polyhalogenated compounds to
alkenes catalyzed by [CuII(tpma)X][X] (X=ClÀ and BrÀ) in the presence
of free-radical initiator V-70 as a reducing agent.
Table 2. (Continued)
Entry[a] Alkene
AHCTUNGTRENNUNG
[b]
RX
G
G
Conv. [%]/
TON[d]
Yield[c] [%]
[b]
Entry[a] Alkene
RX
G
[CuII]0
Conv. [%]/
Yield[c] [%]
TON[d]
32
33
34
35
36
37
38
methyl acry- CCl4
late
~100/84
840
1240
4400
6400
12500
480
CCl4
CBr4
CBr4
CBr4
2000:1 (0.05) ~100/62
1
2
3
4
5
6
7
1-decene
1-octene
1-hexene
styrene
CCl4
CCl4
1000:1 (0.1)
2000:1 (0.05)
10:1 (10)
93/93
81/80
1/0
930
1600
0
4600
7200
17500
2
10000:1 (0.01) ~100/82
20000:1 (0.005) ~100/70
50000:1 (0.002) ~100/63
CHCl3
CBr4
CBr4
CBr4
CHBr3
10000:1 (0.01) ~100/99
CHBr3 1000:1 (0.1)
64/48
47/39
20000:1 (0.005)
50000:1 (0.002)
100:1 (1)
96/89
92/88
2/2
CHBr3 2000:1 (0.05)
780
39
40
41
42
43
44
methyl
methacrylate CCl4
CCl4
1000:1 (0.1)
2000:1 (0.05)
10000:1 (0.01) ~100/71
20000:1 (0.005) ~100/44
~100/66
87/44
660
880
6300
7200
0
8
9
CCl4
CCl4
1000:1 (0.1)
2000:1 (0.05)
10:1 (10)
99/97
87/84
2/0
970
1680
0
4400
7600
18500
2
CBr4
CBr4
10
11
12
13
14
CHCl3
CBr4
CBr4
CBr4
CHBr3
CHBr3 1000:1 (0.1)
CHBr3 2000:1 (0.05)
94/8
96/5
10000:1 (0.01) ~100/~100
0
20000:1 (0.005)
50000:1 (0.002)
100:1 (1)
96/94
92/93
3/2
45
46
47
48
49
50
51
vinyl acetate CCl4
1000:1 (0.1)
2000:1 (0.05)
1000:1 (0.1)
2000:1 (0.05)
5000:1 (0.02)
100:1 (1)
96/94
80/70
95/88
87/87
80/77
7/6
780
1220
610
1200
2500
6
CCl4
CBr4
CBr4
CBr4
CHBr3
CHBr3
15
16
17
18
19
20
21
CCl4
CCl4
1000:1 (0.1)
2000:1 (0.05)
10:1 (10)
96/96
86/85
4/0
960
1700
0
3400
6400
14500
4
CHCl3
CBr4
CBr4
CBr4
CHBr3
10000:1 (0.01) ~100/98
3/3
6
20000:1 (0.005)
50000:1 (0.002)
100:1 (1)
98/96
96/93
4/4
[a] All reactions were performed in CH3CN at ambient temperature
[alkene]0:[V-70]0 =1:1:0.05, except reac-
(22Æ28C) for 24 h with [RX]0:
G
tions for entries 1–7, which were performed in 1,2-dichloroethane.
[b] mol% of copper relative to alkene. [c] Yield is based on the forma-
tion of monoadduct and was determined by 1H NMR spectroscopy using
anisole (styrene) or 1,4-dimethoxybenzene (all other alkenes) as internal
standards. [d] TONs were calculated taking into account the percent
yield of monoadduct for ATRA reactions conducted in the absence of
22
23
24
25
26
27
28
29
30
31
CCl4
CCl4
CCl4
CHCl3
CHCl3
CBr4
CBr4
CBr4
500:1 (0.2)
1000:1 (0.1)
2000:1 (0.05)
100:1 (1)
200:1 (0.5)
200:1 (0.5)
54/51
33/31
22/24
60/48
51/39
96/91
64/57
49/46
86/70
82/61
255
310
480
48
78
[CuII
ACTHNUTRGNE(UNG tpma)X][X] (see Table 1).
124
560
1700
700
1220
2000:1 (0.05)
10000:1 (0.01)
CHBr3 1000:1 (0.1)
CHBr3 2000:1 (0.05)
As mentioned above, ATRA of polyhalogenated com-
pounds to monomers that are highly active in free-radical
polymerization was not very successful at 608C when AIBN
was used as radical initiator. As a result of very high propa-
gation rate constants for monomers such as methyl acrylate,
methyl methacrylate, acrylonitrile, or vinyl acetate, copper-
catalyzed ATRA in the presence of AIBN as a reducing
agent at 608C required high catalyst loadings and/or large
excess of alkyl halide. The results at ambient temperatures
using V-70 as a reducing agent and stoichiometric amounts
of alkene and alkyl halide were quite different. In ATRA of
CCl4 (entry 22) to styrene, the monoadduct was obtained in
51% yield using 0.2 mol% of copper catalyst. On the other
hand, nearly quantitative yield was observed with CBr4
(entry 27) using 0.5 mol% of copper. ATRA reactions with
styrene were also quite successful with less active CHCl3
(entries 25, 26) and CHBr3 (30, 31). Similarly, dramatic im-
provements were also observed in ATRA of CCl4 and CBr4
to methyl acrylate (entries 32, 33 and 34, 36) and methyl
methacrylate (entries 39, 40 and 41, 42). For both mono-
mers, ATRA of CCl4 and CBr4 proceeded very efficiently at
Figure 1. ACHTUNTRGNENGU ACHTUNTGERN(NUGN tpma)Br][Br] catalyzed ATRA of CBr4 to 1-hexene in the
[CuII
presence of V-70 at 22Æ28C with a) 0.002, b) 0.01, c) 0.05, d) 0.1, e) 1.0,
and f) 10 mol% of copper. For all experiments, the conversion of 1-
hexene was ~100% and the yield of monoadduct >93%.
ambient temperature using catalyst loadings as low as 0.1
and 0.005 mol%, respectively. As evident from Table 2 (en-
tries 37, 38) ATRA of CHBr3 to methyl acrylate also yielded
the desired monoadduct with 0.1 and 0.05 mol% of copper.
Furthermore, CHBr3 was quite inactive alkyl halide in
copper-catalyzed ATRA of methyl methacrylate (entries 43,
44). Although high monomer conversions were obtained,
they were mostly attributed to polymer formation.
The methodology for catalyst regeneration in copper-
mediated ATRA in the presence of V-70 as a reducing
agent also worked very well in the addition of CCl4 and
40
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Chem. Eur. J. 2009, 15, 38 – 41

Atom-Transfer Radical Addition
COMMUNICATION
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copper catalyst, respectively. However, similarly to methyl
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In summary, highly efficient, ambient-temperature ATRA
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ACHTUNGTRENNUNG
[CuII(tpma)X][X] (X=BrÀ and ClÀ) complexes in the pres-
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Acknowledgements
Financial support from Duquesne University (start-up grant and faculty
development grant) and National Science Foundation NMR grant (NSF
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Keywords: atom-transfer radical addition
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· catalysis ·
[25] Values were calculated assuming [alk]0 =1.8m, 1.8ꢂ10À5
m
(0.001 mol%)<[Cu]0 <1.8ꢂ10À3
108 mÀ1 sÀ1
m
(0.01 mol%) and kd =1.0ꢂ
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Received: October 4, 2008
Published online: November 25, 2008
Chem. Eur. J. 2009, 15, 38 – 41
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
41