Deuteration enhances catalyst lifetime in palladium-catalysed alcohol oxidation

Article abstract of DOI:10.1039/c5cc08588h

The catalyst palladium/2,9-CD₃-phenanthroline has a 1.8 times higher turnover number than its non-deuterated counterpart in the aerobic alcohol oxidation of methyl glucoside and allows the regioselective oxidation with dioxygen as the terminal oxidant.

Full text of DOI:10.1039/c5cc08588h

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Deuteration enhances catalyst lifetime in
palladium-catalysed alcohol oxidation†
Cite this:DOI: 10.1039/c5cc08588h
Nicola Armenise, Nabil Tahiri, Niek N. H. M. Eisink, Mathieu Denis, Manuel Jager,
¨
Johannes G. De Vries, Martin D. Witte and Adriaan J. Minnaard*
Received 15th October 2015,
Accepted 16th December 2015
DOI: 10.1039/c5cc08588h
www.rsc.org/chemcomm
The catalyst palladium/2,9-CD3-phenanthroline has a 1.8 times
higher turnover number than its non-deuterated counterpart in
the aerobic alcohol oxidation of methyl glucoside and allows the
regioselective oxidation with dioxygen as the terminal oxidant.
Palladium-catalyzed alcohol oxidation is an important method
for the preparation of aldehydes and ketones, in particular in
complex substrates.1 Waymouth et al.2 recently reported that
cationic palladium/neocuproine complexes3 catalyze the chemo-
selective oxidation of vicinal diols to a-hydroxy ketones at room
temperature. In particular, the secondary hydroxyl group is oxidized
by [(neocuproine)Pd(OAc)]2[OTf]2 (1) with excellent selectivity
and yield.4
Scheme 1 Ligand oxidation in palladium-catalyzed aerobic alcohol
oxidation.
Extending this work, we showed that 1 is also able to discriminate develop oxidation resistant 2,9-disubstituted phenanthroline
between different secondary hydroxyl groups in the first catalytic, ligands, but with limited success. Also, Waymouth et al. reported
regioselective oxidation of unprotected pyranosyl glucosides to a mono-trifluoromethyl substituted phenanthroline ligand and
the corresponding ketosaccharides.5
studied it in the palladium-catalyzed oxidation of 2-heptanol.2c
Although designed, and effective, for aerobic oxidation, the The turnover number of this catalyst doubled, and no ligand
reactions using air or dioxygen require high Pd loadings up to oxidation was observed, however at the cost of a 3.7 times lower
10 mol%.2,4 This is caused in part by concomitant autoxidation initial rate compared to 1. Furthermore, the ligand is difficult to
of the ligand (Scheme 1). Oxidation of a methyl substituent via access.
C–H insertion of Pd(II) hydroperoxide (4), followed by subsequent
further oxidation, forms an inactive palladium complex (6).
Oscillating between the requirement of substituents and
their desired resistance against C–H activation we realized that
With other terminal oxidants, such as benzoquinone, oxidation deuteration of the methyl groups in neocuproine could enhance
of the ligand is much slower and the turnover number of 1 is the stability of the palladium catalyst against autoxidation to
therefore considerably enhanced. However, the use of oxygen or air such an extent that the aerobic alcohol oxidation, in particular
is highly desirable, in particular for carbohydrate oxidation, as it of carbohydrates, would become feasible. The lower zero-point
strongly simplifies the isolation of the products.
energy of the deuterium–carbon bond compared to the hydrogen–
The presence of substituents at the 2 and 9 position of the carbon bond (around 5 kJ molꢀ1) results in a higher activation
phenanthroline ligand is critical. In this way, the dimeric pre-catalyst energy for C–D bond cleavage manifested as a kinetic isotope
is in equilibrium with the active monomeric catalyst in solution. effect.6,7 Consequently, the deuterated catalyst should be more
Palladium complexes ligated by unsubstituted phenanthrolines stable without changing its properties in catalysis.
are inactive at room temperature. Therefore, efforts were made to
The approach is reminiscent to deuteration strategies in
drug development, that are used to enhance the stability of a
drug in oxidative metabolism.8 In synthesis, deuteration has
been applied in specific cases to alter reaction selectivity.9 To
the best of our knowledge, a deuteration strategy to increase
ligand stability in catalysis, however, has not been reported.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7,
9747 AG Groningen, The Netherlands. E-mail: A.J.Minnaard@rug.nl
† Electronic supplementary information (ESI) available: Experimental procedures,
and spectral characterization. See DOI: 10.1039/c5cc08588h
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Table
1
Deuterated versus non-deuterated neocuproine in the
palladium-catalyzed aerobic oxidation of 2-heptanol (12)a
Scheme 2 Regioselective aerobic oxidation of methyl a-D-glucopyranoside
at room temperature.
Entry
Solvent
Pd cat.
Conv.b (%)
TON
TOFe (hꢀ1
)
1
2
3
4
DMSO
1-d12
1-d12
1-d12
1
81
100c
68d
84
13.5
17
Max (23)
Max (14)
13
19
—
20
DMSO/H2O
DMSO/H2O
DMSO/H2O
In order to go beyond proof of principle, deuteration of the
ligand should be straightforward. Browne et al. have described
a practical perdeuteration of bipyridine and phenanthroline
ligands with NaOD/D2O at high temperature.10 More recently,
a
Reaction conditions: 12 (1 mmol, 0.5 M), O2 (1 atm), Pd cat. (3 mol%),
b
solvent, rt, 24 h. Conversion determined by GC-MS (ratiometric
method, see ESI). After 14 h. Reaction conditions: 12 (2 mmol,
1 M), O2 (1 atm), Pd cat. (1.5 mol%), DMSO/H2O (1 mol% with respect
to DMSO), rt, 24 h. After 30 h the conversion had not changed. TOF
c
d
¨
Neranon and Ramstrom used a similar method to exclusively
e
deuterate the methyl moieties, employing microwave heating.11
Herein we report that deuteration of neocuproine leads to a
significant increase in turnover number in the aerobic palladium-
catalyzed oxidation of methyl glucoside (7) and allows this
reaction to be carried out using oxygen as the sole terminal
oxidant (Scheme 2).
determined by interpolation of reaction progress curves, see ESI.
mono-alcohol oxidation and that water, produced by oxygen
reduction, does not inhibit the catalyst. In fact, the addition of
molecular sieves even leads to a lower initial rate and conversion.2a
Therefore, the oxidation of 12 (0.5 M) in DMSO in the presence
of 1 mol% of water (with respect to DMSO) was evaluated. Under
these conditions, 1-d12 showed a higher TOF (19 hꢀ1) compared to
the reaction in pure DMSO, and full conversion of 12 was reached
in 14 h (entry 2, Table 1). Although an explanation for this
improvement is currently lacking, we attribute it to this solvent
system (Fig. 1).
Subsequently, the maximum turnover number for the deuterated
catalyst was determined by doubling the amount of substrate to
prevent complete conversion. The oxidation of 12 (1 M) catalyzed
by 1-d12 (1.5 mol%) resulted in 68% conversion of 2-heptanol
after 24 h (TON = 23).
Compared to the activity of 1-d12, complex 1 shows a similar
TOF (20 hꢀ1) but during the course of the reaction the rate
decreases to afford 84% conversion after 24 h (entry 4, Table 1).
Since the oxidation of 12 with catalyst 1 did not result in full
conversion, the maximum turnover number of 1 could be
directly determined (TON = 14). The comparison of the reaction
curves highlights the improved stability of the new deuterated
neocuproine palladium complex 1-d12 in the oxidation of mono-
alcohols, against non-deuterated 1 (Fig. 2) and the increase in
maximum turnover number for 1-d12 over 1 underlines this
further.
Deuteration of the methyl groups of neocuproine was carried
out according to the procedure reported for a similar substrate,
6,60-dimethyl-2,20-bipyridine.11 Treatment of 9 with aqueous
sodium deuteroxide at 190 1C for 180 min in a microwave
provided 9-d6 in 99% isotopic purity and 92% isolated yield.
The degree of deuteration was determined by NMR using the
residual solvent peak as internal standard.
In their early work,2a Waymouth et al. found that compro-
portionation of (neocuproine)Pd(OAc)23a and the ditriflate analogue
(neocuproine)Pd(MeCN)2(OTf)212 in acetonitrile afforded the dimeric
acetate-bridged complex [(neocuproine)Pd(m-OAc)]2[OTf]2 1, which
could be isolated and used in aerobic alcohol oxidations. Later,
it was shown that dimer formation can be carried out in situ
preceding the catalysis, and we followed the latter method for
the preparation of the deuterated catalyst.2c The new deuterated-
neocuproine palladium precursor complexes 10-d6 and 11-d6 were
prepared similar to their non-deuterated analogues. Complexation
of ligand 9-d6 with palladium acetate gave 10-d6 in 87% yield (pure
according to NMR and elemental analysis), and subsequent
treatment of 10-d6 with triflic acid furnished 11-d6 in 93% yield
(pure according to NMR, see ESI†).
In order to accurately determine the difference in activity
between the deuterated and the non-deuterated catalyst, first,
the oxidation of 2-heptanol under an oxygen atmosphere at room
temperature was studied as a model reaction. This reaction is
readily monitored by GC-MS, contrary to the oxidation of methyl
a-D-glucopyranoside.
As the goal was aerobic oxidation of carbohydrates, which is
carried out in DMSO, we chose this solvent also for the
oxidation of 2-heptanol (12, 1 mmol, 0.5 M). Deuterated catalyst
1-d12 (3 mol% of the Pd dimer) prepared in situ from the
deuterated complexes 10-d6 and 11-d6 (3 mol% each) exhibited
a turnover frequency (TOF) of 13 hꢀ1. The conversion was 81%
after 24 h (TON = 13.5, entry 1, Table 1). Waymouth and
coworkers reported that the addition of water has an accelerating
Fig. 1 Reaction progress curves for the aerobic oxidation of 2-heptanol (12)
with catalyst 1-d12 in DMSO ( ) and in DMSO/H2O ( ) at room temperature.
effect on the rate of diol oxidation, but not on the rate of The reaction was carried out in quadruplo and the mean values were plotted.
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of 1-d12 in the oxidation of glucopyranosides as well. The TON for
1-d12 was determined by doubling the amount of glucopyranoside.
The oxidation of 7 (1 M) catalyzed by 1-d12 (1.5 mol%) resulted in
53% conversion of a-D-glucopyranoside after 24 h (TON = 18).
For both substrates 7 and 12, turnover numbers of the
deuterated catalyst are increased by a factor of at least 1.6
compared to the non-deuterated catalyst.
Concluding, the straightforward deuteration of the methyl
substituents in neocuproine allowed the development of a catalyst
system (1-d12) that increased the turnover number in aerobic
alcohol oxidation with at least 1.6 times and for methyl glucoside
with 1.8 times. The turnover frequency of the catalyst is similar, as
expected, but as inactivation of the catalyst by intramolecular C–H
activation is retarded due to the kinetic isotope effect, the catalyst
1-d12 has a longer lifetime. The increase in turnover number allows
the aerobic oxidation of glycosides with acceptable catalyst loadings
and this is a major practical advantage compared to the use
of benzoquinone, as purification of the oxidation products is
considerably simplified.
Fig. 2 Reaction progress curves for the aerobic oxidation of 2-heptanol (12)
with catalysts 1-d12
( ) and 1 ( ) in DMSO/H2O at room temperature.
Reactions were carried out in duplo with the mean conversion being plotted.
Table 2 Catalyst efficiency in the selective oxidation of glucopyranoside
(7)a
Deuteration of neocuproine and other pyridine and phenan-
throline-type ligands is so straightforward and inexpensive that
neocuproine-d6 (9-d6) should find application in related catalytic
oxidation reactions as well. Although the problem of ligand
oxidation is not solved in this way, it is significantly relaxed.
We acknowledge the Dutch Science Foundation NWO for
financial support. N. A. acknowledges the University of Bologna
for a Marco Polo research grant. Prof. W. R. Browne is acknowl-
edged for useful discussions.
Entry
Pd cat.
Conv.b (%)
TON
TOFe (hꢀ1
)
1
2
3
1-d12
1
1-d12
100c
58
17
Max (10)
Max (18)
8
7
—
53d
a
Reaction conditions: 7 (1.25 mmol, 0.5 M), O2 (1 atm), Pd cat.
b
(3 mol%), DMSO-d6/D2O, rt, 24 h. Conversion determined by
1H-NMR (ratiometric method, see ESI). After 18 h. Reaction conditions:
c
d
7 (2.5 mmol, 1 M), O2 (1 atm), Pd cat. (1.5 mol%), DMSO-d6/D2O, rt, 24 h.
e
After 30 h the conversion had not changed. TOF determined by Inter-
polation of reaction progress curves, see ESI.
Notes and references
1 I. W. C. E. Arends and R. A. Sheldon, in Modern Oxidation Methods,
¨
ed. J.-E. Backvall, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
2nd edn, 2010.
2 (a) N. R. Conley, L. A. Labios, D. M. Pearson, C. C. L. McCrory and
R. M. Waymouth, Organometallics, 2007, 26, 5447; (b) D. M. Pearson and
R. M. Waymouth, Organometallics, 2009, 28, 3896; (c) D. M. Pearson,
N. R. Conley and R. M. Waymouth, Organometallics, 2011, 30, 1445.
3 (a) G.-J. ten Brink, I. W. C. E. Arends, M. Hoogenraad, G. Verspui and
R. A. Sheldon, Adv. Synth. Catal., 2003, 345, 1341; (b) I. W. C. E. Arends,
G.-J. ten Brink and R. A. Sheldon, J. Mol. Catal. A: Chem., 2006, 251, 246.
4 R. M. Painter, D. M. Pearson and R. M. Waymouth, Angew. Chem.,
Int. Ed., 2010, 49, 9456.
¨
5 M. Jager, M. Hartmann, J. G. de Vries and A. J. Minnaard, Angew.
Chem., Int. Ed., 2013, 52, 7809.
Fig. 3 Reaction progress curves for the oxidation of glucopyranoside (7)
6 E. M. Simmons and J. F. Hartwig, Angew. Chem., Int. Ed., 2012, 51, 3066.
7 After submission of this manuscript a study was reported on the
mechanism of the palladium-catalyzed alcohol oxidation in which
also d6-neocuproine was involved, however not in catalysis, see:
A. J. Ingram, K. L. Walker, R. N. Zare and R. M. Waymouth, J. Am.
Chem. Soc., 2015, 137, 13632.
8 (a) S. L. Harbeson and R. D. Tung, Annu. Rep. Med. Chem., 2011,
46, 403; (b) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529;
(c) A. Katsnelson, Nat. Med., 2013, 19, 656.
9 (a) J. A. Halfen, V. G. Young Jr. and W. B. Tolman, J. Am. Chem. Soc., 1996,
118, 10920; (b) J. Clayden, J. H. Pink, N. Westlund and F. X. Wilson,
Tetrahedron Lett., 1998, 39, 8377; (c) M. Miyashita, M. Sasaki, I. Hattori,
M. Sakai and K. Tanino, Science, 2004, 305, 495; (d) M. E. Wood,
with catalyst 1-d12
temperature. Reactions were carried out in duplo with the mean conver-
( ) and 1 ( ) in DMSO-d6/D2O (1 mol%) at room
sion being plotted.
With these results in hand, we focussed on the oxidation of
methyl a-D-glucopyranoside (7) under the same conditions. As
we reported,5 7 is selectively oxidized at the C3 position and this
1
permits accurate determination of the conversion by H-NMR.
The oxidation of 7 (0.5 M) in DMSO-d6/D2O with 1-d12
(3 mol% Pd cat.) gave a TOF of 8 hꢀ1 and full conversion to the
sole product 8 within 14 h (entry 1, Table 2). Non-deuterated catalyst
1 under the same reaction conditions gave a slightly lower rate
(TOF = 7 hꢀ1) and a considerably lower conversion (58% after 24 h,
´ ´
S. Bissiriou, C. Lowe, A. M. Norrish, K. Senechal, K. M. Windeatt,
S. J. Coles and M. B. Hursthouse, Org. Biomol. Chem., 2010, 8, 4653.
10 W. R. Browne, C. M. O’Connor, J. S. Killeen, A. L. Guckian, M. Burke,
P. James, M. Burke and J. G. Vos, Inorg. Chem., 2002, 41, 4245.
¨
11 K. Neranon and O. Ramstrom, RSC Adv., 2015, 5, 2684.
TON = 10, Fig. 3). These results demonstrate the increased stability 12 E. Drent and P. H. M. Budzelaar, Chem. Rev., 1996, 96, 663.
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