Cu(I)(2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane)+ as a catalyst for Ullmann's reaction

Article abstract of DOI:10.1039/b210018p

Cu(I)L complexes catalyze the Ullmann reaction 2-BrC₆H ₄CO₂^- + H₂O → 2-HOC ₆H₄CO₂^- + Br^- + H ⁺ however the process is slow and undesirable yields of benzoic acid and diphenoic acid are formed. The optimal ligand, L, for this catalyst should enhance the rate of the process, probably via shifting the redox potential of the Cu(II/I) couple cathodically, inhibit the formation of the diphenoic acid, probably via steric hindrance, and of benzoic acid probably via buffering the solution at pH > 7. The results demonstrate that Cu(I)(2,5,8,11-tetramethyl- 2,5,8,11tetraazadodecane)⁺, i.e. Cu(I) with a ligand which fulfils these requirements, is a very good catalyst for this process with a selectivity of > 97% and high turnover numbers. The Royal Society of Chemistry 2003.

Full text of DOI:10.1039/b210018p

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؉
Cu(I)(2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane) as a
catalyst for Ullmann’s reaction†
a
a,b
a,c
Irena Rusonik, Haim Cohen and Dan Meyerstein
a
Chemistry Department, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Nuclear Research Centre Negev, Beer-Sheva, Israel
Biological Chemistry Department, The College of Judea and Samaria, Ariel, Israel
b
c
Received 11th October 2002, Accepted 14th November 2002
First published as an Advance Article on the web 23rd April 2003
Cu()L complexes catalyze the Ullmann reaction
Ϫ
2
Ϫ
Ϫ
ϩ
2
-BrC H CO ϩ H O
2-HOC H CO ϩ Br ϩ H
6 4 2
6
4
2
however the process is slow and undesirable yields of benzoic acid and diphenoic acid are formed. The optimal
ligand, L, for this catalyst should enhance the rate of the process, probably via shifting the redox potential of the
Cu(/) couple cathodically, inhibit the formation of the diphenoic acid, probably via steric hindrance, and of benzoic
acid probably via buffering the solution at pH > 7. The results demonstrate that Cu()(2,5,8,11-tetramethyl-2,5,8,11-
ϩ
tetraazadodecane) , i.e. Cu() with a ligand which fulfils these requirements, is a very good catalyst for this process
with a selectivity of >97% and high turnover numbers.
Introduction
It is well known that Cu() species catalyze the Ullmann
1–6
reaction
and specifically the transformation of 2-bromo-
benzoic acid into salicylic acid with benzoic acid and diphenoic
acid as side products, Scheme 1. A detailed recent mechanistic
3
study suggested that the mechanism of this process involves
the reactions shown in Scheme 2.
Scheme 1
Thus in order to optimize the catalytic process one has to:
(
1) Increase the concentration of Cu() species in the system; in
aqueous solutions this means to use a ligand which prevents the
7
precipitation of CuOH or Cu O, and the disproportionation
2
ϩ
7
of Cu (aq). (2) Cathodically shift the redox potential of the
2
ϩ/ϩ
Cu(/)L couple relative to the Cu
(aq) couple (to increase
8
the rate of the process). (3) Use a ligand which will impose
sufficient steric hindrance to inhibit the formation of diphenoic
acid (which is formed via the reaction of intermediate 6 with
intermediate 5, or 4 in Scheme 2). (4) Decrease the yield of
benzoic acid; the ligand should enable maintainence of a pH of
>
7, thus decreasing the rate of formation of benzoic acid via
ϩ
the reaction of intermediate 4 with H , Scheme 2. Intermediate
might also react with water to yield benzoic acid, this reaction
clearly cannot be inhibited in aqueous solutions.
4
I
ϩ
These considerations led us to study the properties of Cu L ,
L = 2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane, as a cata-
lyst for this process as it is known that: (1) The redox potential
of the Cu(/)L couple is 12 mV at pH 10.0, i.e. it is shifted
cathodically relative to the Cu
Scheme 2
9
2ϩ/ϩ
I
ϩ
(aq) couple. (2) This ligand
The results indeed point out that Cu L is a good catalyst for
this process.
induces considerable steric hindrance around the central copper
ion. (3) As the pK s of this ligand are pK = 9.23, pKa2 = 8.47,
a
a1
8
pKa3 = 5.36 and pKa4 = 1.68 it is a relatively good buffer at
pH > 7.
†
Based on the presentation given at Dalton Discussion No. 5, 10–12th
April 2003, Noordwijkerhout, The Netherlands.
2
024
D a l t o n T r a n s . , 2 0 0 3 , 2 0 2 4 – 2 0 2 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3

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Results
Ϫ
2
Mixing of a solution containing 2-BrC H CO with a solution
6
4
ϩ
containing CuL at pH 10.0 in the stopped-flow resulted in
two observations: (1) An immediate increase in the absorption
at 320 nm, on a time scale faster than the mixing time. This
rise is proportional to [2-BrC H CO ], indicating the fast
formation of an intermediate via the reaction of Cu L with
Ϫ
6
4
2
I
ϩ
Ϫ
2
2
-BrC H CO . (2) A slower reaction with a rate proportional
6
I
4
ϩ
I
ϩ
to [Cu L ]. However, this process is observed also when Cu L
is mixed with H O at pH 10.0, i.e. in the absence 2-BrC -
2
6
Ϫ
2
H CO . It is concluded that the reaction observed is due to
4
some O which penetrates the system during the mixing time.
2
After the reaction with O is over no fast process is observed.
2
These experiments point out that although an intermediate is
I
ϩ
Ϫ
formed via a fast reaction between Cu L and 2-BrC H CO
2
6
4
the formation of salicylic acid is slow and almost unobserved
over the first 1000 seconds. On the other hand the penetration
of some O during the mixing cannot be avoided under our
2
experimental conditions. Therefore it was decided to prepare
I
ϩ
II 2ϩ
0
Cu L in situ via comproportionation of Cu L and Cu in the
presence of excess L and follow the kinetics by measuring the
yield of the organic products using HPLC.
The effect of the addition of L on the rate of the process and
the composition of the products is illustrated in Fig. 1.
Ϫ
Fig. 2 The effect of the substrate, 2-BrC H CO , concentration on
6
4
2
the rate of the process and the selectivity. (a) and (b): 2-bromobenzoic
Ϫ3
Ϫ3
0
acid, CuSO (0.025 mmol dm ), L (0.125 mmol dm ), Cu , pH = 10.0,
4
T = 25 ЊC.
This result is in accord with the expectation for the main
reaction:
Ϫ
2
Ϫ
Ϫ
ϩ
2
-BrC H CO ϩ H O
2-HOC H CO ϩ Br ϩ H
6 4 2
6
4
2
Ϫ
The increases in the yield of C H CO are in accord with
6
5
2
expectations according to the mechanism summed up in
Scheme 2. Indeed analysis of Fig. 2 indicates that most of the
Ϫ
C H CO is formed towards the end of the process, i.e. at
6
5
2
lower pHs. This is even better demonstrated when one com-
pares the results for solutions with an initial pH of 10.0, Fig. 2,
with those with an initial pH of 7.0, Fig. 1, where the yield of
Ϫ
2
2
-HOC H CO is 86.8 and 77.9%, respectively whereas the
6
4
Ϫ
yield of C H CO is 13.2 and 22.1%, respectively.
6
5
2
These results suggest that the process can be improved by
raising the pH and/or by adding a buffer; for pH 10 a 0.125 M
borax buffer was chosen. The effect of pH on the rate of the
process is plotted in Fig. 3. Surprisingly the results point out
that the rate of the process decreases with the increase of
pH though the selectivity of the process increases. This result
Fig. 1 The effect of the addition of L on the rate of the process and
Ϫ3
composition of the products. (a) 2-Bromobenzoic acid (1 mmol dm ),
Ϫ
Ϫ3
0
suggests that OH or the borate anion act as additional ligands
CuSO4 (0.025 mmol dm ), Cu , pH = 7.0, T = 25 ЊC. (b) 2-
Ϫ3
Ϫ3
Bromobenzoic acid (1 mmol dm ), CuSO4 (0.025 mmol dm ),
Ϫ3
0
L (0.125 mmol dm ), Cu , pH = 7.0, T = 25 ЊC.
The results clearly demonstrate that addition of the ligand:
(
1) Accelerates considerably the rate of the process and short-
ens the induction time. (2) Inhibits the formation of diphenoic
acid. (3) Increases the yield of salicylic acid.
Thus it is clear that the addition of L is beneficial and there-
fore experiments to optimize the process were performed.
Ϫ
The effect of the substrate, 2-BrC H CO , concentration on
6
4
2
the rate of the process and the product selectivity is plotted in
Fig. 2.
The results clearly demonstrate that the rate of the process
Ϫ
accelerates considerably with [2-BrC H CO ] whereas the
6
4
2
selectivity decreases. The final pH of the solution also decreases
Fig. 3 The effect of pH on the rate of the process. 2-Bromobenzoic
Ϫ
with the increase in [2-BrC H CO ] being 8.4; 7.5 and 4.8 for
Ϫ3
Ϫ3
Ϫ3
6
4
2
acid (1 mmol dm ), CuSO (0.025 mmol dm ), L (0.125 mmol dm ),
4
Ϫ
2
Ϫ3
0
[
2-BrC H CO ] = 0.25; 0.50 and 1.0 mmol dm , respectively.
Cu , T = 25 ЊC.
6
4
D a l t o n T r a n s . , 2 0 0 3 , 2 0 2 4 – 2 0 2 8
2025

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I
ϩ
to Cu L thus slowing down the process. Alternatively the pH
effect on the rate of the process might be due to its effect on the
rate of the comproportionation reaction, see below.
Alternatively the ligand L can be used as a buffer. Therefore
the effect of its concentration on the rate of the process was
studied, the results are summarized in Fig. 4, the final pH values
are given in the figure. The concentrations of copper ions at the
end of the process were measured by aerating aliquots, thus
I
ϩ
II 2ϩ
oxidizing the C L to Cu L , and measuring the concentration
II 2ϩ
of Cu L by measuring the OD at 666 nm . The results high-
II 2ϩ
light that [Cu L ] is independent of [L], i.e. the effect of [L] on
I
ϩ
the rate of the process is not due to an effect on [Cu L ].
Fig. 6 Determining the apparent activation energy of the process.
Ϫ3
Ϫ3
2
-Bromobenzoic acid (1 mmol dm ), CuSO4 (0.025 mmol dm ),
Ϫ3 0
L (0.375 mmol dm ), Cu , pH = 10.0.
solution and titrating with deaerated 0.1 M NaOH to maintain
constant pH. These experiments were performed at pH 9.0,
Figs. 7 and 8, and at pH 10.0. The results demonstrate that the
process is considerably faster at pH 9.0, Fig. 8, though the
Ϫ
selectivity of the 2-HOC H CO yield, 96.8%, is slightly lower
6
4
2
than at pH 10.0, 97.5%.
Fig. 4 The effect of ligand concentration on the rate of the process.
Ϫ3
Ϫ3
2
-Bromobenzoic acid (1 mmol dm ), CuSO4 (0.025 mmol dm ),
pH = 10.0, T = 60 ЊC.
The results clearly demonstrate that the rate of the process
decreases with the increase in [L] though the selectivity
Ϫ3
increases. The results suggest that L = 0.375 mmol dm is
2ϩ
the optimal concentration for [Cu (aq)]0 = 0.025 mmol
Ϫ3
dm . Under these conditions, at pH = 10.0 the yield of
0
Ϫ
2
-HOC H CO is 96%.
6
4
2
I
ϩ
I
ϩ
The effect of the concentration of Cu L , [Cu L ] =
II 2ϩ
2
[Cu L ] , was studied, the results are plotted in Fig. 5. The
0
Ϫ3
Fig. 7 2-Bromobenzoic acid (10 mmol dm ), CuSO4 (0.025 mmol
results clearly demonstrate that the rate of the process increases
Ϫ3
Ϫ3
0
dm ), L (0.375 mmol dm ), Cu , pH = 9.0, T = 60 ЊC.
I
ϩ
linearly with [Cu L ]. Thus the results demonstrate that the
I
ϩ
I
ϩ
n
initiation step differs for Cu L and Cu (CH CN) where it
3
I
ϩ 2 3
depends linearly on [Cu (CH CN) ] .
3
n
Ϫ3
Fig. 8 2-Bromobenzoic acid (10 mmol dm ), CuSO4 (0.025 mmol
Ϫ3
Ϫ3
0
dm ), L (0.375 mmol dm ), Cu , T = 60 ЊC.
I
ϩ
The results presented in Fig. 8 suggest a relatively long
initiation period. This could be due to the rate of the com-
proportionation reaction. The latter was measured by following
Fig. 5 The effect of the concentration of Cu L . 2-Bromobenzoic
Ϫ3
Ϫ3
0
acid (1 mmol dm ), CuSO , L (0.375 mmol dm ), Cu , pH = 10.0,
T = 25 ЊC. The yield were measured after 4 hours, i.e. after the com-
proportionation reaction was completely finished.
4
II 2ϩ
0
the OD at 284 nm of solutions containing Cu L , L and Cu .
II 2ϩ
This wavelength was chosen because at this point ε(Cu L ) >
I
ϩ
The apparent activation energy of the process was deter-
minated by measuring the yield of 2-HOC H CO 30 min
after the beginning of the process and calculating the initial
rate constant from these yields. The results are summarized in
Fig. 6, from which E (apparent) = 81 ± 5 kꢀ mol is derived.
The results thus suggest that one could obtain larger yields of
-HOC H CO if one starts with higher initial concentrations
of 2-BrC H CO and maintains a constant pH throughout the
ε(Cu L ). The results are plotted in Fig. 9. The results clearly
demonstrate that the comproportionation reaction is consider-
ably faster at pH 9.0. However the rate is considerably higher
than that predicted from the observed initiation period, Fig. 8.
One source for the difference might be the absorbance of
Ϫ
6
4
2
Ϫ1
a
0
the aromatic acid to the Cu surface. In order to check this
Ϫ
2
Ϫ
2
possibility the effect of C H CO on the rate of the compro-
6
4
6
4
2
Ϫ
portionation reaction was measured, Fig. 10. The results clearly
demonstrate that the aromatic acids indeed slow down the
comproportionation process.
6
4
2
Ϫ3
process. This was performed by starting with 10 mmol dm
-BrC H CO and continuously bubbling He through the
Ϫ
2
6 4 2
2
026
D a l t o n T r a n s . , 2 0 0 3 , 2 0 2 4 – 2 0 2 8

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Ϫ
required to abstract a bromide from 2-BrC H CO or to insert
6
4
2
into the Br–C bond.
The latter two observations require that Scheme 2 be replaced
by Scheme 3 in the presence of the ligand L.
Fig. 9 Dependence of the rate of the comproportionation reaction
Ϫ3
Ϫ3
0
on pH. CuSO (0.3 mmol dm ), L (1.5 mmol dm ), Cu , T = 60 ЊC,
4
λ = 284 nm.
Fig. 10 Effect of the aromatic acid on the rate of the compro-
Ϫ3
Ϫ3
0
portionation process. CuSO (1.5 mmol dm ), L (7.5 mmol dm ), Cu ,
4
pH = 10.0, T = 60 ЊC, λ = 646 nm.
Discussion
The results clearly demonstrate that the addition of the ligand
2
ϩ
ϩ
0
L to the reaction mixture containing Cu , Cu , Cu and
Scheme 3
Ϫ
2
-BrC H CO improves the catalytic process. This improve-
6 4 2
ment is three-fold: (1) The addition of the ligand accelerates the
catalytic process, probably by increasing the concentration of
Ϫ
2
The yield of C H CO can be minimized by keeping the pH
6
5
of the system above pH 8 throughout the process. The residual
yield of benzoate, ca. 3%, is probably due to the reaction:
I
the Cu species in the system and by increasing the rate of the
Ϫ
bromide abstraction from 2-BrC H CO , see below. (2) The
6
4
2
addition of the ligand enables high turnovers when one main-
tains a constant pH. (3) The addition of the ligand improves the
Ϫ
selectivity of the process. The yield of 2-HOC H CO is
6
4
2
increased to ca. 97% as compared to 45% in its absence.
Furthermore in the presence of the ligand the formation of
diphenoic acid is totally inhibited. The latter result is probably
due to the steric hindrance imposed by L, inhibiting the
reaction:
This reaction is expected to be considerably slower than the
reaction:
As the heterolysis reactions of metal–carbon bonds in gener-
10–15
II
16
al
and Cu –carbon bonds specifically are known to be
acid catalyzed.
At high pHs or in the presence of excess ligands the process
is slowed down. This observation stems probably from two
sources: (1) The extra ligands slow down the comproportion-
0
ation reaction either via adsorbtion to the surface of Cu or
by ligation to Cu L which stabilizes the Cu() oxidation
3
II 2ϩ
which is the source of diphenoic-acid, Scheme 2.
The results further demonstrate that in the presence of L the
state. (2) The formation of intermediate 1, Scheme 3, probably
requires that the Cu() center will be bound to L at most via
three coordination sites, i.e. one of the terminal amines has to
be released, this happens as an equilibrium process and it is
I
ϩ
process is first order in [Cu L ], after the comproportionation
reaction is over, Fig. 5. This result differs from that observed
I
ϩ
n
when Cu (CH CN) is used as a catalyst where the rate
3
I
2 3
9
depends linearly in [Cu (CH CN) ] . This observation is attri-
known that the fourth amine is bound weakly to the copper.
3
n
Ϫ
buted to the considerable cathodic shift of the Cu(/) couple
The additional ligands, including OH , are expected to
I
ϩ
Ϫ
when L replaces (CH CN) . Therefore one Cu L only is
compete with 2-BrC H CO for this coordination site.
3
n
6
4
2
D a l t o n T r a n s . , 2 0 0 3 , 2 0 2 4 – 2 0 2 8
2027

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It should be noted that under our experimental conditions
the rate determining step, at least in the initiation phase of the
process, is the comproportionation reaction.
Finally it is tempting to suggest that L, or analogous ligands,
will be beneficial additives to other processes catalyzed by Cu()
species, which do not require a large space in the vicinity of the
central copper ion.
resolution). A Merck 50943 LiChroCart 125–4, LiChrospher
100 RP-18 (5 µm) column was utilized. A mixture of 35%
MeCN (HPLC grade) and 65% 0.05 M phosphate buffer at pH
Ϫ1
3.5 was used as the eluent at a rate of 0.5 ml min ; chromato-
grams were thus collected within 8 min. Calibration for starting
materials and possible products were performed at 220, 260 and
295 nm (area of peaks) if applicable.
I
؉
Determination of [Cu L ] in the reaction mixture. Aliquots of
Experimental
0
the solution, not containing any Cu , were aerated and the
II 2ϩ
concentration of Cu L thus formed was determined at
Materials
6
66 nm where only the latter complex has an absorption band.
All the chemicals used in this study were of A.R. grade,
purchased from Aldrich and Merck. Solutions were prepared
in distilled water which was further purified by passing through
Acknowledgements
Ϫ1
a Milli Q Millipore setup, final resistivity > 10 MΩ cm . The
This study was supported in part by a grant from the Budgeting
and Planning Committee of The Council of Higher Education
and the Israel Atomic Energy Commission. D. M. wishes to
express his thanks to Mrs Irene Evens for her ongoing interest
and support.
ligand L was purchased from Aldrich. All solutions were
strictly deaerated using the syringe technique and He gas. When
deaerated solutions had to be mixed, a solution from one
syringe was injected into a second syringe via a three way valve.
Aqueous solutions of the aromatic acids were prepared by
completely dissolving the solids in basic, NaOH solutions and
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4
I
ϩ
Cu L was prepared by deaerating a solution containing
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-BrC H CO , L, CuSO and then adding, during He
6
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4
0
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I
ϩ
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Ϫ
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4
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(
4
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1
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1
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2
028
D a l t o n T r a n s . , 2 0 0 3 , 2 0 2 4 – 2 0 2 8