Transcript Highly Efficient Copper Mediated Atom Transfer Radical

Highly Efficient Copper Mediated Atom
Transfer Radical Addition and
Cyclization Reactions in the Presence of
Reducing Agents
Tomislav Pintauer
Department of Chemistry and Biochemistry
Duquesne University
Pittsburgh, PA 15282
12th Annual Green Chemistry and Engineering Conference, Washington DC
1
Introduction and Background
• Carbon-carbon bond formation is a fundamental reaction in
•
organic synthesis.
One way to form such a bond and, thus, extend a carbon chain
is by the addition of a polyhalogenated alkane to an alkene to
form a 1:1 adduct:
CX3Y
+
R'
R' H
H
X
R
H
CX2Y
R H
X=halogen; Y=H, halogen, CF3, or other electronegative group
• This reaction was first reported in the 1940s and today is known
•
as Kharasch addition or atom transfer radical addition (ATRA).
Historically, ATRA reactions were conducted in the presence of
radical initiators and light (high yields of monoadduct for ATRA
of CX4 to  -olefins, but low for styrene and methyl acrylate).
Curran, D. P. Synthesis 1988, 6, 417.
Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128.
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Kharasch Addition Reaction
• Free Radical Mechanism
• Initiated by light or radical
initiators (e.g. AIBN)
Initiation:
AIBN
-Unavoidable radical-radical
coupling reactions (kt≈1.0×109
M-1s-1)
-Repeating radical addition to
alkene to generate
oligomers/polymers
-Low chain transfer constant
(ktr/kp)
• SOLUTIONS:
+ N2
CN
• PRINCIPLE
PROBLEMS:
CN

+ Br3C
CN
ki
Br
Propagation:
CBr3
kadd
+
R
Br3C
Br3C
R
n
R
Br3C
+ Br3C
R
Br
ktr
Br
R
Br3C
R
monoadduct
+ CBr3
Termination:
radical-radical coupling
kt
CBr3 + CBr3
CN
CN
+
Br3C
etc.
Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128.
R
kp
kt
Br3C
R
+ Br3C
CBr3
CN
-Search for better halogen
transfer agents (transition metal
complexes)
+ CBr3
Br
CN
kt
R
R
Br3C
CBr3
R
3
Transition Metal Catalyzed (TMC) ATRA
• Transition metal complexes of Fe, Ru, Co, Ni and Cu are
•
particularly effective halogen transfer agents.
Variety of alkenes and alkyl halides can be utilized.
ka,1
K1=
R
ka,2
K2=
kd,1
kd,2
X
CuILmX
X
R
R'
TO ACHIEVE HIGH YIELDS:
R
ka,1
ka,2
kd,1
R'
kp
CuIILmX2
R
R
R'
R
R'
R
kt
R'
n
kd,2
kt
R'
R
R
R
kadd
R'
L=complexing ligand
X=halide or pseudo halide
- Radical concentration must be
low (ka,1 and ka,2<<kd,1 and kd,2)
- Further activation of the
monoadduct should be avoided
(ka,1>>ka,2 and ka,2≈0)
- The formation of
oligomers/polymers should be
suppressed
(kd,2[CuIILmX]>>kp[alkene])
R etc.
Minisci, F. Acc. Chem. Rec. 1975, 8, 165.
Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
Severin, K. Curr. Org. Chem. 2006, 10, 217.
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TMC ATRA in Organic Synthesis
• Can be conducted intermolecularly and intramolecularly.
• Atom transfer radical cyclization (ATRC) particularly attractive
tool because it enables synthesis of functionalized ring systems.
-lactones and -lactams
Cl
CCl3
O
O
CH3CN, 110
oC
CuCl (30 mol%)
Cl
Cl
O
Domino TMC ATRA
O
16 h
95% yield
O
Cl
CCl3
O
Cl
Cl
Cl
O
O
Cl
OEt
DCE, 80 oC
CuCl/bpy (25 mol%)
O
Cl OEt
H
18 h
N
O
CH3CN, RT
N
Cl
61% yield
CuCl/bpy (5 mol%)
15 min
SO3CH3
SO3CH3
91% yield
Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
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Current Drawbacks of TMC ATRA
• TMC ATRA despite being discovered nearly 40 years before tin
•
•
•
mediated radical addition to olefins and iodine atom transfer
radical addition is still not fully utilized as technique in organic
synthesis.
The principal reason is that TMC ATRA typically requires
between 5 and 30 mol% of catalyst relative to alkene.
Problems in product separation and catalyst recycling.
Process is environmentally unfriendly and expensive.
Methodologies developed to overcome these drawbacks:
Design of solid supported catalysts
•Use of biphasic systems (fluorous solvents)
•Development of highly active complexes based on ligand
design
•Catalyst regeneration in the presence of reducing agents✓
Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
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Catalyst Regeneration in the Presence of
Reducing Agents
• The rate of alkene consumption in ATRA depends on the ratio of
concentrations of activator (CuI) and deactivator (X-CuII):
d[M]

 kp [M][R] 
dt
kpK ATRA [M][RX][Cu I]
[X  CuII]
• Deactivator accumulates during the process as a result of
•
radical termination reactions.
 agents can be used to regenerate activator.
Reducing
ka,1
MtnLm + R X
kd,1
•Originally developed for atom
Mtn+1LmX + R
kt
R R
CN
X
1.
2.
3.
4.
CN

N2
AIBN
transfer radical polymerization
(ATRP).
•Successfully adopted to ATRA
catalyzed by copper(II) and
ruthenium(III) complexes.
Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem. 2007, 563-571.
Eckenhoff, W. T.; Pintauer, T. Inorg. Chem. 2007, 46, 5844-5846.
Quebatte, L.; Thommes, K.; Severin, K. J. Am. Chem. Soc. 2006, 128, 7440-7441.
Matyjaszewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W. A.; Tsarevsky, N. V. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 1530915314.
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I
Cu (TPMA)Cl
ATRA Catalyzed by
Complex in the
Presence of Reducing Agent AIBN
TPMA
•
•
•
Can be conducted using either copper(I) or copper(II) complex.
TONs for 1-octene (4350-6700) and 1-hexene (4900-7200) highest so far for copper
mediated ATRA.
Previous TONs ranged between 0.1 and 10!
Eckenhoff, W. T.; Pintauer, T. Inorg. Chem. 2007, 46, 5844-5846.
8
I
Cu (TPMA)Cl
ATRA Catalyzed by
Complex in the
Presence of Reducing Agent AIBN
9
ATRA Catalyzed by [CuII(TPMA)Br][Br] Complex
in the Presence of Reducing Agent AIBN
[Alkene]0:[CuII]0
/
Yield (%)
32
2
200,000:1
81(76)
TON
/
1.6×10
3
100,000:1
94
9.4×10
/
72
5
200,000:1
95(86)
/
1.9×10
6
100,000:1
99
9.9×10
1,000:1
57
5.7×10
500:1
66
3.3×10
10,000:1
70
7.0×10
10
5,000:1
77
3.9×10
11
1,000:1
92
9.2×10
61(59)
6.1×10
Entry
Alkene
RBr
1
methyl acrylate CBr4
4
7
styrene
CBr4
methyl acrylate CHBr3
8
9
styrene
CHBr3
12 W. T.; Garrity,
1-hexene
10,000:1
Eckenhoff,
S. T.; Pintauer,CHBr
T. Eur. J.3Inorg. Chem.
2007, 563-571.
5
4
5
4
2
2
3
•
•
Highest TONs for
copper mediated
ATRA
Highly efficient
ATRA in the
presence of 5100 ppm of
copper
3
2
3
10
Reaction Kinetics for ATRA of CCl4 to Alkenes
Kinetics for 1-Octene
Copper(II)
120
3
0
t
0
0
100:1
500:1
1000:1
2.5
ln([M] /[M] )
% Yield of Monoadduct
II
[1-octene] :[Cu ]
2
1.5
100
80
60
40
20
0
1
1-octene
styrene
methyl acrylate
0
2000
4000
6000
8000
0
0.5
1.2 10
4
5000
1 10
4
1.5 10
4
2 10
4
2.5 10
4
3 10
Tim e / s
Constant concentration of radicals
Apparent rate constant relatively
independent on copper(II) concentration
Rate governed by AIBN decomposition
4
% Yield of Monoadduct
0
0
AIBN
120
0
•
4
II
[alkene] :[Cu ]
•
•
1 10
100
80
60
40
1-octene
styrene
methyl acrylate
20
0
0
0.05
0.1
0.15
0.2
mol% AIBN (relative to alkene)
0.25
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I
Cu (TPMA)Cl
Structural Features of
and
II
[Cu (TPMA)Cl][Cl] Complexes
CuI(TPMA)Cl
[CuII(TPMA)Cl][Cl]
• Copper(I) and copper(II) complexes are structurally similar.
Eckenhoff, W. T.; Pintauer, T. Inorg. Chem. 2007, 46, 5844-5846.
12
I
Cu (TPMA)Br
Structural Features of
and
II
[Cu (TPMA)Br][Br] Complexes
CuI(TPMA)Br
[CuII(TPMA)Br][Br]
• Copper(I) and copper(II) complexes are structurally similar.
Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem. 2007, 563-571.
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Structural Features of CuI(TPMA)Br in Solution
1H
NMR
400 MHz, (CD3)2CO
• Low T 1H NMR consistent
with X-ray structure.
Proton / ppm
H1
0.60
H2
0.12
H3
0.05
H4
-0.32
H5
0.10
• Broadening of the spectra is
induced by fluxional
processes:
1. TPMA dissociation
2. Br- dissociation
• Dimer formation unlikely
(inequivalent methylene
protons).
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Structural Features of
I
[Cu (TPMA)]2[ClO4]2
• First example of a dimer where one arm of TPMA ligand
coordinates to the second metal center
1H
NMR
(400 MHz, (CD3)2CO)
Distorted Tetrahedral
Cu1-N1=2.2590(13) Å
Cu1-N2=1.9909(12) Å
Cu1-N3=2.2213(16) Å
Cu1-N4=1.9593(13) Å
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Structural Features of
I
[Cu (TPMA)(CH
1H
Axial elongation
of Cu-N bond
3CN)][BPh4]
NMR
(400 MHz, (CD3)2CO)
90% [CuI(TPMA)(CH3CN)][BPh4]
10% [CuI(TPMA)]2[BPh4]2
180 K
[CuI(TPMA)]2[ClO4]2
[CuI(TPMA)(CH3CN)[BPh4]
Similar to CuI(TPMA)X
Cu1-N1=2.069(6) Å
Cu1-N2=2.430(6) Å
Cu1-N3=2.077(6) Å
Cu1-N4=2.122(6) Å
Cu1-N5=1.990(6) Å
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Solution Equilibria for CuI(TPMA)X Complexes
• Addition of TBABr sharpens 1H NMR spectrum.
• Addition of TPMA sharpens 1H NMR spectrum (fast exchange).
• Coordination of CH3CN observed. 298 K
1. Halide dissociation
2. TPMA arm dissociation
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Cyclic Voltammetry Studies
• The role of halide anion coordination to [CuI(TPMA)]+ remains
•
unclear.
Nature of ATRA (ISET or OSET)?
Inner Spere Electron Transfer
[R---X---MtnLm]
R-X + MtnLm
R + X-Mtn+1Lm
Outer Spere Electron Transfer
[RX-
R-X + MtnLm
R + X-] + Mtn+1Lm
R + X-Mtn+1Lm
• Equilibrium
constant for ATRA can be expressed in terms of:
K
ET
MtnLm
X + e
R-X
Electron Transfer
Mtn+1Lm + e
KEA
Electron Affinity
X
KBH
X + Mtn+1Lm
MtnLm
Bond Homolysis
R + X
+ RX
KHP
For a given alkyl halide
KATRA will depend on
KET and KHP
KATRA=KEAKBHKHPKET
Mtn+1LmX
KATRA
Halidophilicity
KATRA
Mtn+1L
mX
+ R
KEAKBH
= KETKHP
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Correlating Redox Potential with Catalyst Activity
More Reducing CuIBr Complexes
Higher Activity in ATRA
N
N
N
N
N
N
R
N
R
N
N
N
N
R
N
N
R
N
N
0
-50
R
N
N
N
N R
-100
N
-150
-200
-250
-300
-350
N
N
-400
-450
-500
E1/2 / mV v.s. SCE
Qiu, J.; Matyjaszewski, K.; Thouin, L.; Amatore, C. Macromol. Chem. Phys. 2000, 201, 1625-1631.
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Cyclic Voltammetry of [CuI(TPMA)][A] Complexes
Complex
Supp. Elect.
E1/2 /mV
ΔEp / mV
ipa/ipc
[CuI(TPMA)][ClO4]
TBAClO4
-422
94
0.95
TBABr
-706
97
0.92
TBAPF6
-421
88
0.94
TBABr
-711
88
0.91
TBABr
-720
93
1.08
[CuI(TPMA)][PF6]
CuI(TPMA)Br
Potentials are reported vs. Fc/Fc+.
• Coordination of bromide anion to
•
[CuI(TPMA)]+ results in a
formation of much more
reducing CuI(TPMA)Br complex.
Kinetically, all complexes
showed similar reactivity in
ATRA (rate determining step is
the decomposition of AIBN).
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Conclusions and Future Outlook
• Synthesis, characterization and exceptional activity of
•
•
•
•
[CuII(TPMA)X][X] (X=Br- and Cl-) complexes in ATRA of
polyhalogenated compounds to alkenes in the presence of
reducing agent AIBN was presented.
[CuII(TPMA)Br][Br] in conjunction with AIBN effectively catalyzed
ATRA of CBr4 and CHBr3 to alkenes with concentrations
between 5 and 100 ppm, which is the lowest number achieved
in copper mediated ATRA.
Counterion was found to greatly affect the redox potential of
copper(I) complexes.
Structural and mechanistic studies of this interesting catalytic
system are subject to further study.
Possible extension to synthetically more attractive ATRC
reactions (including radical cascade reactions) is also
considered.
21
Acknowledgements
Group Members
Marielle Balili
3rd Year Graduate Student
William Eckenhoff
2nd Year Graduate Student
Carolynne Ricardo
2nd Year Graduate Student
Financial Support
Duquesne University Start-Up Fund
Duquesne University Faculty Development Fund
NSF X-ray Facility Grant (CRIF 0234872)
NSF NMR Facility Grant (CHE 0614785)
Petroleum Research Fund (PRF 44542-G7)
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Duquesne University-Department of Chemistry
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