Ti(IV)-based catalytic membranes for efficient and selective oxidation of secondary amines

Article abstract of DOI:10.1016/j.tetlet.2004.07.142

The incorporation of homogenous Ti(IV)/trialkanolamine catalyst in polymeric membranes provided new polymeric catalytic Ti(IV)-based membranes, stable and efficient as heterogeneous catalysts for chemoselective oxidations of secondary amines to nitrones by alkyl hydroperoxides. Polyvinylidene fluoride (PVDF)-based catalytic membranes gave the best results affording products in short reaction times, high yields and selectivity using as little as 1% of catalyst, comparable with the performances of the corresponding homogeneous system. PVDFa€"Ti membrane could be recycled up to five runs with no loss of activity.

Full text of DOI:10.1016/j.tetlet.2004.07.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7515–7518
Ti(IV)-based catalytic membranes for efficient and
selective oxidation of secondary amines
Maria Giovanna Buonomenna,a Enrico Drioli,a William A. Nugent,c Leonard J. Prins,b
Paolo Scriminb and Giulia Licinib,
*
a
`
Dip. di Ingegneria Chimica e Materiali, Universita della Calabria and ITM–CNR, via Bucci 17/C,
I-87030 Arcavacata Di Rende, CS, Italy
b
`
Dip. Scienze Chimiche, Universita di Padova, ITM–CNR, Sezione di Padova, via Marzolo 1, I-35131, Padova, Italy
cBristol Myers Squibb Co., Process Research and Development Department, Princeton, NJ 08543, USA
Received 12 June 2004; revised 28 July 2004; accepted 29 July 2004
Abstract—The incorporation of homogenous Ti(IV)/trialkanolamine catalyst in polymeric membranes provided new polymeric cat-
alytic Ti(IV)-based membranes, stable and efficient as heterogeneous catalysts for chemoselective oxidations of secondary amines to
nitrones by alkyl hydroperoxides. Polyvinylidene fluoride (PVDF)-based catalytic membranes gave the best results affording prod-
ucts in short reaction times, high yields and selectivity using as little as 1% of catalyst, comparable with the performances of the
corresponding homogeneous system. PVDF–Ti membrane could be recycled up to five runs with no loss of activity.
Ó 2004 Elsevier Ltd. All rights reserved.
Chemical processes catalysed by homogeneous transi-
tion metal complexes are increasingly utilized in the fine
and basic chemical industry. The majority of such metal
catalysts is often expensive, of limited environmental
compatibility, or even toxic. The current trend towards
a sustainable chemistry has given life to an increasing
number of new strategies for catalyst immobilization,
enabling an easy recovery, re-use and disposal at low
costs of the catalyst.1 A possible solution could be the
use of catalytic polymeric membranes in which no cata-
lyst recovery is required, reaction and separation of the
products are coupled, catalysts may have longer life and
the intact structure of the catalyst should be preserved
inside the polymeric membranes, minimizing any change
in activity and selectivity versus the homogeneous sys-
tem.2 As a proof of principle, Ru–BINAP,3 Rh–DU-
PHOS4 and Jacobsen catalyst for epoxidation of
simple olefins3 were entrapped in polydimethylsiloxane
matrices affording performances comparable to the
analogous homogeneous systems.2 As far as oxygen
transfer catalysis is concerned, the Sharpless–Katsuki
epoxidation system5 launched the rich field of titanium
catalyzed asymmetric oxidations.6 Since that break-
through, chiral Ti(IV) alkoxides have been used to cata-
lyze a variety of oxidative transformations affording
highly stereoselective processes in the allylic alcohol
epoxidation,5 b-hydroxyamine N-oxidation,7 sulfoxida-
tion,8 as well as in the Baeyer–Villiger oxidation of
cyclobutanones.9
We have recently reported that tetradentate alkoxide
ligands, namely C3-symmetric trialkanolamines 1,10
provide very stable Ti(IV) complexes (Fig. 1).11 In the
presence of alkyl hydroperoxides, such species are able
to catalyze the asymmetric sulfoxidation of alkyl aryl
sulfides with eeÕs up to 84% and with unprecedented cat-
alytic efficiency, reaching turnover numbers (TON) of
100012 as well as the oxidation of secondary amines to
R1
OH
Ph
OR
R1OOH
O
O
O
Ti(iPrO)4
Ph
Ph
Ph
O
Ti
O
Ph
Ph
O
N
Ti
O
HO
O
Ph
N
Ph
N
Ph
OH
(R,R,R)-1
(R,R,R)-2
(R,R,R)-3
Keywords: Catalytic membranes; Nitrones; Ti(IV)-complexes; Trialk-
anolamines; N-Oxidation.
Figure 1. Synthesis of titanatrane complex (R,R,R)-2 and the corre-
sponding peroxocomplex (R,R,R)-3 by reaction of (R,R,R)-tris-(2-
phenylethanol)amine 1 with Ti(i-PrO)4.
*
Corresponding author. Tel.: +39 0498275289; fax: +39
0498275239; e-mail: giulia.licini@unipd.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.142

7516
M. G. Buonomenna et al. / Tetrahedron Letters 45 (2004) 7515–7518
Table 1. Effect of the catalyst on reaction times and product
distribution in the Ti-catalyzed oxidation of dibenzylamine with CHPa
nitrones with high chemoselectivities, quantitative yields
and TON up to 1400.13
Ti(IV)(10%)
Beside the fact that the oxygen transfer process affords
in both cases the corresponding products with high
chemical yields and good selectivities, the Ti(IV) catalyst
was shown to be robust under the reaction condi-
tions, which require the presence of large quantities of
alkylperoxide12 and, in the case of secondary amine oxi-
dation, affords a stoichiometric amount of water.13
Therefore, titanatrane complex 2 seemed to us a good
candidate for preparing Ti(IV) polymeric catalytic mem-
branes to be used in selective oxygen transfer reac-
tions.14 Because of their intrinsic stability they should
survive the conditions required for the membrane syn-
thesis. Once in the polymeric matrix, their stability
should be even higher because secondary hydrolysis
reactions will be minimized, extending catalyst life.
Obviously, the effective recycling of the catalytic mem-
brane will increase the total TON of the process.
Bn Bn Bn
Bn
O
N
OH
5a
N
O
6a
Ph
+
4a
+
+
Ph
N
+ CHP
Ph
H
60°C, MeCN
7a
8
Time (h)
Catalyst (product ratio: 4a:5a:6a:7a:8)
PVDF–Ti PAN–Ti PEEKWC–Ti
38:12:44:6:0 54:6:25:11:4 92:1:6:1:0
Ti-2
3
4:5:74:5:3
7
1:4:78:4:13 0:7:82:5:6
49:6:27:12:7 82:1:14:3:0
9:0:40:18:33 58:1:34:7: 0
43:2:34:14:6
25
117
a Reaction conditions: [substrate]0 = 0.1M; [CHP]0 = 0.4M, cata-
lyst = 10%mol; CD3CN; T = 60°C. ms.
PEEK-WC in chlorinated solvents, which are the most
suitable ones for the homogeneous reactions, the reac-
tivity was initially explored in acetonitrile and the course
of the reactions was monitored via H NMR. Prelimi-
nary tests on the catalytic membranes indicated that cat-
alyst leaching was not a severe problem.20
Here we report on the successful preparation of different
catalytic membranes incorporating Ti(IV)-complex 2
and their successful application for heterogeneous oxi-
dation of secondary amines to nitrones.15
1
In Table 1 the product distributions at increasing reac-
tion times for the oxidations catalyzed by PVDFD–Ti,
PEEKWC–Ti, PAN–Ti and by the Ti-2 homogeneous
system are reported.
The preformed Ti(IV) (R,R,R)-tris-(2-ethanol)amine
complex11 (16%/w) has been entrapped in three different
polymeric membranes using a phase inversion technique
induced by a non-solvent (DMA and water, respec-
tively).16 Polymers characterized by a high thermal,
chemical and mechanical stability were used for the
preparation of catalytic membranes: polyvinylidene
difluoride (PVDF),17 a modified polyether-etherketone
(PEEK-WC)18 and polyacrylonitrile (PAN).19
Significantly, all three Ti-based catalytic membranes
could activate CHP for the oxygen transfer process
although the polymeric matrix plays an important role
in determining performance and product distribution.
Reactions performed with PAN–Ti and PEEK-WC–Ti
gave slow conversions of the reagent affording the nit-
rone in comparable amounts with N-benzylidene benzyl-
amine and benzaldehyde. Furthermore, at long reaction
times high amount of benzaldehyde were recovered due
to further oxidation/hydrolysis of the products. On the
contrary, PVDF–Ti efficiently catalyses the oxidation
affording the nitrone in good yields (82%) in reasonable
reaction times, almost comparable to the ones of the
homogeneous system.21
O
O
O
H2
C
H
C
CN
H2 F2
C
C
n
n
O
O
n
PVDF
PAN
PEEK-WC
The screening of activity of the different catalytic mem-
branes [PVDF–Ti, PEEKWC–Ti, PAN–Ti] has been as-
sessed in the oxidation to nitrones of dibenzylamine,
chosen as a model substrate (Fig. 2).
The oxidation with catalytic membrane PVDF–Ti was
also tested in chloroform. The kinetic profile of the reac-
tion is reported in Figure 3.
The performance of the catalytic membranes was inves-
tigated under batch conditions using an equal active sur-
face and comparable total catalyst loading. In order to
have a better comparison of the results, the reactions
were carried out under the best conditions selected for
the homogeneous reactions. Due to the solubility of
In chloroform the reaction occurs much faster [t1/2
(CDCl3) = 65min vs t1/2 (CH3CN) = 140min] and the
nitrone was recovered in high chemical yield (92%) with
almost complete chemoselectivity (only traces of imine
and hydroxylamine were detected).
The performance of the PVDF–Ti catalytic membrane
has been also evaluated on the basis of system recycling.
A set of experiments was carried out in order to examine
its activity along five oxidation runs. After each experi-
ment the membrane was removed from the reaction ves-
sel, washed in chloroform in order to remove adsorbed
(R,R,R)-2
(R,R,R)-2
Ph
NH
2
Ph
N
O
Ph
Ph
NOH
2
+ CHP
- H2O
+ CHP
Figure 2. Chemoselective oxidation of dibenzyl amine by cumyl
hydroperoxide (CHP) catalyzed by Ti(IV) complex (R,R,R)-2.

M. G. Buonomenna et al. / Tetrahedron Letters 45 (2004) 7515–7518
7517
Table 3. Effect of substrate/catalyst ratio on oxidation of dibenzyl-
amine catalyzed by PVDF–Ti membrane or the homogeneous catalyst
Ti(IV)-2 in CDCl3 at 60°Ca
100
75
50
25
0
amine 7
nitrone 9
[Sub]0, M
0.1
Sub/cat
10:1
Catalyst
Time (h)
Nitrone (%)
Ti-2b
PVDF–Ti
3
2.5
100
92
1.0
1.0
100:1
Ti-2b
PVDF–Ti
1
3
100
90
hydroxylamine 8
1000:1
Ti-2b
PVDF–Ti
100
71
68c
65d
0
100
200
300
400
Time, min
a Conditions: dibenzylamine: CHP = 4:1, 4A molecular sieves in
CDCl3 at 60°C.
˚
Figure 3. Oxidation of dibenzylamine with CHP catalyzed by PVDF–
Ti catalytic membrane: [substrate]0 = 0.1M; [CHP]0 = 0.4M, cata-
lyst = 10%mol; T = 60°C, ms = 250mg/mmol in CDCl3: (d) dibenzyl-
amine; (n) dibenzylhydroxylamine; (m) nitrone.
b See Ref. 13.
c Complete reagent conversion; other products: N-benzylidene benz-
ylamine (15%), PhCHO (15%).
d Complete reagent conversion; other products: N-benzylidene benz-
ylamine (10%), PhCHO (22%), 1,2-dichloroethane as solvent.
Table 2. Oxidation of dibenzylamine with CHP catalyzed by PVDF–
Ti, catalyst recycling: substrate: [substrate]0 = 0.1M; [CHP]0 = 0.4M,
catalyst = 10%mol; T = 60°C, CDCl3, ms = 250mg/mmol in run 1,
500mg/mmol runs 2–5a
The conditions for the highest catalyst loading (10%)
from Table 2 were adopted to explore the scope of the
reaction with other secondary amines (Table 4).22
Run
Time1/2 (min)
Nitrone (%)
In all cases nitrones were readily isolated in synthetically
significant chemical yields (80–93%) via removal of the
solvent under vacuum followed by chromatography
over silica gel.
1
2
3
4
5
39
10
14
14
23
92
90
90
90
90
a In the recycling, the presence of twice amount of ms proved to be
beneficial in decreasing the formation of benzaldehyde.
In conclusion, novel heterogeneous oxidation catalysts
have been synthesized by embedding Ti(IV)–trialkanol-
amine complexes within polymeric membranes. The
reactivity studies allowed us to: (i) identify the PVDF–
Ti catalytic membrane as the most reactive and stable
system where the catalyst structure is preserved from
hydrolysis; (ii) exclude the occurrence of competing
homogeneous pathways due to catalyst leaching; and
(iii) verify the stability of the embedded catalyst during
recycling. We feel that the prospects for further and
more general applications for the new PVDF–Ti cata-
lytic membranes are excellent and we plan to pursue this
research. Studies directed at the characterization of the
catalytic membrane, especially the nature of the catalyst
embedded in the polymeric matrix, are currently
underway.
reagent or products, and recycled. The results are re-
ported in Table 2.
It is noteworthy that the catalytic activity of the PVDF–
Ti membrane was maintained for all five runs, affording
comparable yields of nitrone (90%) and that, indeed,
catalyst leaching does not seem a severe problem. Inter-
estingly, reaction rates in the recycling experiments were
higher than the first one. The increased reactivity could
originate from modifications of the polymeric mem-
brane that render available a larger quantity of the cat-
alyst or enhance the Lewis acidity of the metal complex.
This important aspect will be addressed in future
studies.
The effect of catalyst loading for the PVDF–Ti mem-
brane was also tested at substrate/catalyst ratios from
10:1 to 1000:1 (Table 3).
Table 4. Catalytic oxidation of secondary amines by CHPa
Substrate
Product
T1/2 (min)
Yield (%)b
Ph
N
H
Ph
n-Bu
Ph
N
O
Ph
39
92
The results reported in Table 3 show that complete con-
version of dibenzylamine and >90% selectivity for the
nitrone could be achieved also in the presence of 1%
of catalyst. It is noteworthy that, in order to maintain
the catalyst concentration at 0.01M, these reactions
were performed neat. However, further increasing the
ratio to s/c = 1000 (which necessarily dropped the cata-
lyst concentration to 0.001M) resulted in a severe dete-
rioration of chemoselectivity, as was also observed in the
homogeneous system.13
n-Bu
n-Bu
N
O
n-Pr
N
50
20
80
93
H
N
O
Ph
N
Ph
H
a Reaction conditions: [substrate]0 = 0.10M, [CHP]0 = 0.40M; cata-
˚
lyst = 10%mol, 4A ms, CHCl3 at 60°C.
b Based on isolated product after chromatography. Reactions were
carried out on mmol scale.

7518
M. G. Buonomenna et al. / Tetrahedron Letters 45 (2004) 7515–7518
K.; Moens, N.; Parton, R.; Reddy, J. S.; Jacobs, P. Chem.
Commun., 1997, 137.
Acknowledgements
15. For a recent example of secondary amine oxidation
catalyzed by heterogenized H3PW12O40 see: Yamata, Y.
M. A.; Tabata, H.; Ichinohe, M.; Takahashi, H.; Ikegami,
S. Tetrahedron 2004, 60, 4087.
L.J.P. acknowledges the financial support provided
through the European CommunityÕs Human Potential
Programme under contract HPRN-CT-2001-00187,
[AC3S]. We gratefully acknowledge MIUR (Cofin2002
16. Typical phase inversion process induced by non-solvent
procedure for flat sheet PVDF, PAN and PEEKWC based
membranes synthesis: to a 10.0wt% solution of the
polymer in dimethylacetammide (DMA, 74wt%) pre-
formed complex Ti-2 (16wt%) was added and the result-
ing solution was left under stirring for 24h: The solution
was cast on a glass plate by setting the knife gap at 250lm,
and the cast film was immediately immersed in a coagu-
lation bath containing distilled water at 15°C. After
10min the membrane was removed from the coagulation
bath and stored in distilled water for 24h, in order to
remove completely DMA. The membrane was dried under
vacuum at 60°C for 24h: Smolders, C. A.; Reuvers, A. J.;
Boom, R. M.; Wienk, I. M. J. Membr. Sci. 1992, 73,
259.
prot.
2002033184_001,
and
Cofin2003,
prot.
2003037580) for financial support. The support and
sponsorship concerted by COST Action D24 ÔSustaina-
ble Chemical Processes: Stereoselective Transition
Metal-Catalysed ReactionsÕ (WG D24/0005/02) are also
kindly acknowledged.
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20. Preliminary tests on the catalytic membranes indicated
that catalyst leaching was not a severe problem. In fact,
after washing the membrane twice with the solvent of the
reaction, no significant amount of catalyst or free trialk-
anolamine ligand could be detected anymore in solution
via 1H NMR. Furthermore, reactions performed under
standard conditions in the presence of the polymeric
material but without Ti(IV) catalyst, resulted in no
significant conversion of the dibenzyl amine into
products.
21. The successful use of PVDF as polymeric membrane for
occluding homogeneous catalysts for photooxidation
(polytungstate) has recently also been reported: Bonchio,
M.; Carraro, M.; Scorrano, G.; Fontananova, E.; Drioli,
E. Adv. Synth. Catal. 2003, 345, 1119.
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have been previously occluded in polydimethylsiloxane
membranes and successfully used for hexane oxidation
and cyclooctene epoxidation: Vankelecom, I.; Vercruysse,
22. Typical oxidation procedure with PVDF–Ti catalysis: in a
25mL screw-cap vial, under nitrogen, containing 10mL of
˚
CHCl3 and 250mg of 4A activated molecular sieves was
added an amount of PVDF-membrane containing
0.1mmol of Ti-2, followed by CHP (4.0mmol, 80% in
cumene) and, after 30min, by the substrate (1.0mmol).
The solution was heated at 60°C and the reaction course
was monitored via TLC. After the disappearance of the
reagent, the membrane was removed, solvent was distilled
under vacuum and the reaction mixture was purified
directly via radial chromatography over silica gel (gradi-
ent: ethyl ether, petroleum ether).