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Molecular imprinting polymerised catalytic complexes in asymmetric catalysis
517
MOLECULAR IMPRINTING POLYMERISED CATALYTIC COMPLEXES IN ASYMMETRIC CATALYSIS
F. Locatelli^, P. Gamez, M. Lemaire* Institut de Recherches sur la Catalyse, CNRS, Laboratoire de Catalyse et Synthese Organique, UCBL 1 /CPELyon, FRANCE 43 Boulevard du II Novembre 1918, 69622 Villeurbanne Cedex, Tel. : (33) 72 43 14 07 Fax : (33) 72 43 14 08
1. INTRODUCTION With the recent progresses in molecular imprinting, one can consider this as a new tool for the synthesis of enantioselective material applicable to both chromatography separation and catalyst preparation [1]. For example, using non covalent bonding, Mossbach et al. have prepared a stationary phase for HPLC in order to resolve (±)-timolol [2]. MIP's havefiinctionalgroups arranged in such a manner that they are complementary in shape and electronic features to the template. Therefore, Wulf et al. have selectively prepared L-Threonine with an enantiomeric excess of 36% by using a polymer which was imprinted with L-DOPA [3]. 1.1 Hydride transfer reduction The target reaction in this study is the reduction of prochiral ketones. In order to do this, we chose to use hydride transfer reduction to reduce phenyl alkyl ketones. This technique is attractive because high pressure and the use of H2 can be avoided. Reduction is carried out using a hydride donor solvent (mainly isopropanol). Under basic conditions, in presence of a rhodium catalyst, ketones are reduced in alcohol and isopropanol is oxidised in acetone. O
II
[OT
OH
OH
^ ^
[RhJIin*
1^
O
tBuOK/iPrOH
Figure I : hydride transfer reduction of phenyl alkyl ketone
The use of chiral ligands within the rhodium complex can render the catalyst enantioselective. For example Gladiali et al. have reduced acetophenone 2 to (S)-l-phenylethanol (ee 63%, yield 89%) using a catalyst having chiral alkyl phenantroline ligands [4].
Present address : Laboratoire de Chimie Organometallique de Surface, UMR CNRS-CPE 69616 Villeurbanne Cedex, FRANCE
518 2. RESULTS We have previously shown that N,N'-dimethyl-l,2-diphenylethanediamine 1 is a good ligand due to the fact that, in this case, the nitrogen atoms are stereogenic centres. It was first used in homogeneous catalysis [5] , then as a monomer to prepare chiral polyureas on which rhodium was deposited [6]. Finally, it was used to prepare a diamine-rhodium complex (similar to the homogeneous one) that was then polymerised. Ph
CH3HN
Ph
NHCH3
1 Figure II: N,N'-dimethyl-l,2-diphenylethanediamine Reducing acetophenone to phenyl-ethanol, polymerised (R,R) rhodium complex allows a lower selectivity of the same enantiomer to that observed in homogeneous phase (homogeneous reduction e.e. (S) 55%, heterogeneous reduction e.e. (S) 33%). 2.1 Molecular imprinting effect We wish to use the "molecular imprinting effect" to obtain highly enantioselective catalytic reaction. The new catalyst preparation allows us to polymerise the chiral rhodium complex in presence of optically pure l-(s)-phenylethanol as a template. A Typical procedure for imprinted polymerised rhodium complex synthesis is : in a round bottom flask under inert dry atmosphere of argon, 750mg (3.12mmol) of (1S,2S)-N,N'dimethyl-l,2-diphenylethane diamine 8 are dissolved in 4 ml of dichloromethane fi-eshly distilled from P2O5. 78 mg (0.32mmol) of catalytic precursor ([Rh(C8Hi2)Cl]2) are added and the solution stirred. Preparation of sodium 1-phenylethanolate : 9 mg (O.33mmol) of NaH 98% are introduced in a second round bottom flask. Then, 1.5 ml of dichloromethanefi-eshlydistilledfi^omP205.and 36^1 (0.3mmol) of optically pure (R)-l-phenylethanol are added. This solution is stirred for one hour before being introduced into the flask containing the rhodium complex. After two hours stirring, a solution of diisocyanate (13a or 13b) and triisocyante ([-C6H3(NCO)CH2-]n n=3 Aldrich 11,130-9) in 1.5 ml of dichloromethane is added. The polyaddition is exothermic. The solution is stirred overnight at room temperature. The solvent is evaporated and the polymer is crushed and washed with 500ml of 2-propanol during 24 hours. Finally it is filtrated through a Millipore filter (w type, pore size O.lOjim). Elimination is monitored by GC on a chiral Cydex B SGE column, 25m x 0.25mm with the other enantiomer as internal reference, dried and sifted. Only particles with a size between 80 and 120jim were retained. Elemental analysis of the solvent shows no evidence for the presence of rhodium, therefore, it can be assumed that no leaching of the metal occurs.
519
Ph \
Ph
[Rh(cod)CI]2
/
H3C—N^
ONC-R-CNO
/Nf-CH3
'^V,
HH
H •CH3
CHjClj, r.t. overnight under argon
8
M >\ /U
,Nh—C—NH—R—O
N—C—NH—R-
Scheme I: Molecular Imprinted Polymer preparation Whereas the non templated polymer gives a selectivity of 33% e.e. (*S)-phenyl-ethanol, the imprinted-polymerised [bis-((R,R)-diamine l)-l-(5)-phenylethoxy-rhodium] complex allows an increase of 10% e.e. in imprinted alcohol. The utilisation of [bis-((R,R)-diamine l)-l-(/?)phenylethoxy-rhodium] complex shows a slight decrease of e.e.. These results may represent an imprinting effect. To be sure that the increase of enantioselectivity observed is not due to the leaching of residual template, we have performed reduction onto propiophenone ((C6H5)COC2H5) since we already knew that non-imprinted complexes are selective for this compound [7] . A similar increase of 19% e.e. between un-imprinted and imprinted polymer is observed. This cannot be due to any leaching as (±)-l-phenyl-propanol is not present in the initial catalyst. Further trials were then carried out using (R)-l-phenylethanol as the template and propiophenone as the substrate to ensure that observed enantioselectivity was only due to the selectivity of the system. 2.2 Influence of cross-linker quantity Being a tri functional group molecule, triisocyanate is used as a cross-linking agent. The degree of cross-linking affects the stiffness of the MIP. It seems that the best compromise between activity and selectivity is obtained with a cross-linking ratio of 50/50 [8]. We then obtain an enantiomeric excess of 70%. 2.3 Influence of temperature and swelling of the polymer Increasing the temperature increases the selectivity of the reaction. This can be explained by the fact that the hot solvent (isopropanol) makes the polymer expand and then "core" sites can be reached by the substrate. There, cavities have a better defined shape making the system more selective. Therefore reaction should be performed at 60°C rather than at room temperature. The swelling-selectivity relationship is not absolute, the use of a very polar solvent such as N,N-dimethylacetamide, leads to such a swelling of the polymer that no more selectivity is observed. Thus, one can assume that this increase of selectivity is due to an
520 equilibrium between accessibility of the best defined sites of the system and stiffiiess of these sites. The activity-swelling relationship is corroborated by the fact that the polymer is more active if it is left for one hour in hot solvent before starting the reaction rather than if the reaction is started as soon as catalyst is in the reactor. The pre-expansion period is once again to the benefit of activity. 2.4 Mechanism We always obtain linear graphs (whatever the value of the parameters) for yield versus conversion graphs. Consequently, one can assume that the synthesis of the two enantiomers occurs via two parallel reactions on the same site without any interconversion. We have therefore proposed the following mechanism (Scheme II) : propiophenone approaches the hydride rhodium complex (described by Gladiali [4]) facing its Si or Re side. This leads to two different complexes and gives (R) or (S) phenyl propan-1-ol. The shape and electronic features of the cavity where the rhodium complex is, should influence the activation energy of these intermediates, thus promoting one of them to react much faster than the other(the one that is created by the Si side approach). (R)-l-phenylpropanol synthesis is favoured.
(R)-Ph6nyl propan-2al
(S)-Ph^yl propan-2oi
Scheme n : Proposed mechanism of reaction 2.5 Selectivity and Activity of MIP on different substrates We have then reduced substrates with structure similar of that of the acetophenone (Table I). Conditions were : 60°C temperature, one hour pre-expansion, cross-linking ratio 50/50, [tBuOK]/[Rh] = 6 (Table I). It can be seen that for 4'-trifluoromethyl acetophenone (entry 4), the initial rate is higher than for the other compounds. It seems that there is an activation of the ketone group by the three fluorine atoms through the aromatic ring. At the other end, no conversion was observed for isopropyl-formiate-benzoyle (entry 3). This can be attribute to the low activity of the a-keto-ester-group or because of the insolubility of the molecule in the polymer. Moving from propiophenone to butyrophenone (entry 2), activity goes down from 18.3 to 14.7 mmol.h"\g"^ of Rh. We can say that the longer the lateral chain the lower the reactivity. For entries (1) and (4) we have obtained an imprinted effect. The selectivity is different and depends of the structure of the substrate. An increase of 22 points was observed for propiophenone and of 8 points for 4'-trifluoromethyl acetophenone. The lower imprinting effect for 4'-trifluoromethyl acetophenone could be explained by the structure being less similar to that of acetophenone than with the propiophenone, and because of the high activity of the molecule. Not only are molecular imprinted polymers more selective, but they are also more active (5 to 10 times higher).
521 For propyl-phenyl ketone (entry 2) a decrease of 14% e.e. on the selectivity was observed. This can be explained by the structure of this compound which is too far from the acetophenone one. A mismatch effect is observed. Table I : Hydride transfer reduction of different substrates Entry
Substrates
imprinted Polymer e.e.(R) initial speed
non imprinted Polymer initial speed e.e.(R) mmol.h "^g"^ of Rh
mmol.h"^g"^ of Rh O
1
2
3
0 0
18.3
70
1.46
48
14.7
44
5.2
58
-
-
-
-
64
38
10
30
0
o
dlVr 0
1
3. Conclusion Polymerised preformed [(N,N'-dimethyl-l,2-diphenylethane diamine)2Rh] complex allows us to obtain enantioselective material. We have then shown that it is possible to imprint an optically pure template into the rhodium-organic matrix and to use the heterogeneous catalyst in asymmetric catalysis with an obvious template effect. The study of yield versus conversion graphs has shown that the mechanism occurs via two parallel reactions on the same site without any inter-conversion of the final products. Adjusting the cross-linker ratio at 50/50 allows us to find a compromise between activity and selectivity. Phenyl ethyl ketone (propiophenone) was reduced quantitatively in 2 days to (R)-l-phenyl propanol with 70% enantiomeric excess We have then shown that the imprinting effect is obvious for molecules related in structure to the template (propiophenone, 4'-trifluoromethyl acetophenone). It is not efficient if the structure of the substrate is too different to that of the template. Further experiments using these materials and on polymers prepared without chiral monomers are under investigation. 4. REFERENCES [1] G. Wulf, Arigew. Chem. Int. Ed Engl., (1995), 34, 1812-1832. [2]
L. Fisher, R. Muller, B. Ekberg and K. Mosbach, J. Am. Chem. Soc, (1991), 113, 9358-9360.
[3]
G. Wulf and J. VietmQiQr,Makromol. Chem., (1989), 190, 1727-1735.
522 [4]
a) S. Gladiali, L. Pinna, G. Delogu, S, De Martin, G. Zassinovich and G. Mestrioni, Tetrahedron : Asymmetry, (1990), 1, 635. b) G. Zassinovich, G. Mestrioni and S. Gladiali, Chem. Rev. , (1992), 92, 1051-1069.
[5]
P. Gamez, F. Fache, P Mangeney and M. Lemaire, Tetrahedron Lett, (1993), 34, 68976898.
[6]
P. Gamez, B, Dunjic, F. Fache and M. Lemaire,./ Chem. Soc, Chem. Commitn, (1994), 1417.1418.
17]
P. Gamez, B. Dunjic, C. Pinel and M. Lemaire, Tetrahedron Lett, (1995), 36, 87798782.
[8]
ratio calculated as below : cross-linking ratio = [sum of fimctional groups from triisocyanates] I [sum of functional groups from diisocyanates]
MOLECULAR IMPRINTING POLYMERISED CATALYTIC COMPLEXES IN ASYMMETRIC CATALYSIS
F. Locatelli^, P. Gamez, M. Lemaire* Institut de Recherches sur la Catalyse, CNRS, Laboratoire de Catalyse et Synthese Organique, UCBL 1 /CPELyon, FRANCE 43 Boulevard du II Novembre 1918, 69622 Villeurbanne Cedex, Tel. : (33) 72 43 14 07 Fax : (33) 72 43 14 08
1. INTRODUCTION With the recent progresses in molecular imprinting, one can consider this as a new tool for the synthesis of enantioselective material applicable to both chromatography separation and catalyst preparation [1]. For example, using non covalent bonding, Mossbach et al. have prepared a stationary phase for HPLC in order to resolve (±)-timolol [2]. MIP's havefiinctionalgroups arranged in such a manner that they are complementary in shape and electronic features to the template. Therefore, Wulf et al. have selectively prepared L-Threonine with an enantiomeric excess of 36% by using a polymer which was imprinted with L-DOPA [3]. 1.1 Hydride transfer reduction The target reaction in this study is the reduction of prochiral ketones. In order to do this, we chose to use hydride transfer reduction to reduce phenyl alkyl ketones. This technique is attractive because high pressure and the use of H2 can be avoided. Reduction is carried out using a hydride donor solvent (mainly isopropanol). Under basic conditions, in presence of a rhodium catalyst, ketones are reduced in alcohol and isopropanol is oxidised in acetone. O
II
[OT
OH
OH
^ ^
[RhJIin*
1^
O
tBuOK/iPrOH
Figure I : hydride transfer reduction of phenyl alkyl ketone
The use of chiral ligands within the rhodium complex can render the catalyst enantioselective. For example Gladiali et al. have reduced acetophenone 2 to (S)-l-phenylethanol (ee 63%, yield 89%) using a catalyst having chiral alkyl phenantroline ligands [4].
Present address : Laboratoire de Chimie Organometallique de Surface, UMR CNRS-CPE 69616 Villeurbanne Cedex, FRANCE
518 2. RESULTS We have previously shown that N,N'-dimethyl-l,2-diphenylethanediamine 1 is a good ligand due to the fact that, in this case, the nitrogen atoms are stereogenic centres. It was first used in homogeneous catalysis [5] , then as a monomer to prepare chiral polyureas on which rhodium was deposited [6]. Finally, it was used to prepare a diamine-rhodium complex (similar to the homogeneous one) that was then polymerised. Ph
CH3HN
Ph
NHCH3
1 Figure II: N,N'-dimethyl-l,2-diphenylethanediamine Reducing acetophenone to phenyl-ethanol, polymerised (R,R) rhodium complex allows a lower selectivity of the same enantiomer to that observed in homogeneous phase (homogeneous reduction e.e. (S) 55%, heterogeneous reduction e.e. (S) 33%). 2.1 Molecular imprinting effect We wish to use the "molecular imprinting effect" to obtain highly enantioselective catalytic reaction. The new catalyst preparation allows us to polymerise the chiral rhodium complex in presence of optically pure l-(s)-phenylethanol as a template. A Typical procedure for imprinted polymerised rhodium complex synthesis is : in a round bottom flask under inert dry atmosphere of argon, 750mg (3.12mmol) of (1S,2S)-N,N'dimethyl-l,2-diphenylethane diamine 8 are dissolved in 4 ml of dichloromethane fi-eshly distilled from P2O5. 78 mg (0.32mmol) of catalytic precursor ([Rh(C8Hi2)Cl]2) are added and the solution stirred. Preparation of sodium 1-phenylethanolate : 9 mg (O.33mmol) of NaH 98% are introduced in a second round bottom flask. Then, 1.5 ml of dichloromethanefi-eshlydistilledfi^omP205.and 36^1 (0.3mmol) of optically pure (R)-l-phenylethanol are added. This solution is stirred for one hour before being introduced into the flask containing the rhodium complex. After two hours stirring, a solution of diisocyanate (13a or 13b) and triisocyante ([-C6H3(NCO)CH2-]n n=3 Aldrich 11,130-9) in 1.5 ml of dichloromethane is added. The polyaddition is exothermic. The solution is stirred overnight at room temperature. The solvent is evaporated and the polymer is crushed and washed with 500ml of 2-propanol during 24 hours. Finally it is filtrated through a Millipore filter (w type, pore size O.lOjim). Elimination is monitored by GC on a chiral Cydex B SGE column, 25m x 0.25mm with the other enantiomer as internal reference, dried and sifted. Only particles with a size between 80 and 120jim were retained. Elemental analysis of the solvent shows no evidence for the presence of rhodium, therefore, it can be assumed that no leaching of the metal occurs.
519
Ph \
Ph
[Rh(cod)CI]2
/
H3C—N^
ONC-R-CNO
/Nf-CH3
'^V,
HH
H •CH3
CHjClj, r.t. overnight under argon
8
M >\ /U
,Nh—C—NH—R—O
N—C—NH—R-
Scheme I: Molecular Imprinted Polymer preparation Whereas the non templated polymer gives a selectivity of 33% e.e. (*S)-phenyl-ethanol, the imprinted-polymerised [bis-((R,R)-diamine l)-l-(5)-phenylethoxy-rhodium] complex allows an increase of 10% e.e. in imprinted alcohol. The utilisation of [bis-((R,R)-diamine l)-l-(/?)phenylethoxy-rhodium] complex shows a slight decrease of e.e.. These results may represent an imprinting effect. To be sure that the increase of enantioselectivity observed is not due to the leaching of residual template, we have performed reduction onto propiophenone ((C6H5)COC2H5) since we already knew that non-imprinted complexes are selective for this compound [7] . A similar increase of 19% e.e. between un-imprinted and imprinted polymer is observed. This cannot be due to any leaching as (±)-l-phenyl-propanol is not present in the initial catalyst. Further trials were then carried out using (R)-l-phenylethanol as the template and propiophenone as the substrate to ensure that observed enantioselectivity was only due to the selectivity of the system. 2.2 Influence of cross-linker quantity Being a tri functional group molecule, triisocyanate is used as a cross-linking agent. The degree of cross-linking affects the stiffness of the MIP. It seems that the best compromise between activity and selectivity is obtained with a cross-linking ratio of 50/50 [8]. We then obtain an enantiomeric excess of 70%. 2.3 Influence of temperature and swelling of the polymer Increasing the temperature increases the selectivity of the reaction. This can be explained by the fact that the hot solvent (isopropanol) makes the polymer expand and then "core" sites can be reached by the substrate. There, cavities have a better defined shape making the system more selective. Therefore reaction should be performed at 60°C rather than at room temperature. The swelling-selectivity relationship is not absolute, the use of a very polar solvent such as N,N-dimethylacetamide, leads to such a swelling of the polymer that no more selectivity is observed. Thus, one can assume that this increase of selectivity is due to an
520 equilibrium between accessibility of the best defined sites of the system and stiffiiess of these sites. The activity-swelling relationship is corroborated by the fact that the polymer is more active if it is left for one hour in hot solvent before starting the reaction rather than if the reaction is started as soon as catalyst is in the reactor. The pre-expansion period is once again to the benefit of activity. 2.4 Mechanism We always obtain linear graphs (whatever the value of the parameters) for yield versus conversion graphs. Consequently, one can assume that the synthesis of the two enantiomers occurs via two parallel reactions on the same site without any interconversion. We have therefore proposed the following mechanism (Scheme II) : propiophenone approaches the hydride rhodium complex (described by Gladiali [4]) facing its Si or Re side. This leads to two different complexes and gives (R) or (S) phenyl propan-1-ol. The shape and electronic features of the cavity where the rhodium complex is, should influence the activation energy of these intermediates, thus promoting one of them to react much faster than the other(the one that is created by the Si side approach). (R)-l-phenylpropanol synthesis is favoured.
(R)-Ph6nyl propan-2al
(S)-Ph^yl propan-2oi
Scheme n : Proposed mechanism of reaction 2.5 Selectivity and Activity of MIP on different substrates We have then reduced substrates with structure similar of that of the acetophenone (Table I). Conditions were : 60°C temperature, one hour pre-expansion, cross-linking ratio 50/50, [tBuOK]/[Rh] = 6 (Table I). It can be seen that for 4'-trifluoromethyl acetophenone (entry 4), the initial rate is higher than for the other compounds. It seems that there is an activation of the ketone group by the three fluorine atoms through the aromatic ring. At the other end, no conversion was observed for isopropyl-formiate-benzoyle (entry 3). This can be attribute to the low activity of the a-keto-ester-group or because of the insolubility of the molecule in the polymer. Moving from propiophenone to butyrophenone (entry 2), activity goes down from 18.3 to 14.7 mmol.h"\g"^ of Rh. We can say that the longer the lateral chain the lower the reactivity. For entries (1) and (4) we have obtained an imprinted effect. The selectivity is different and depends of the structure of the substrate. An increase of 22 points was observed for propiophenone and of 8 points for 4'-trifluoromethyl acetophenone. The lower imprinting effect for 4'-trifluoromethyl acetophenone could be explained by the structure being less similar to that of acetophenone than with the propiophenone, and because of the high activity of the molecule. Not only are molecular imprinted polymers more selective, but they are also more active (5 to 10 times higher).
521 For propyl-phenyl ketone (entry 2) a decrease of 14% e.e. on the selectivity was observed. This can be explained by the structure of this compound which is too far from the acetophenone one. A mismatch effect is observed. Table I : Hydride transfer reduction of different substrates Entry
Substrates
imprinted Polymer e.e.(R) initial speed
non imprinted Polymer initial speed e.e.(R) mmol.h "^g"^ of Rh
mmol.h"^g"^ of Rh O
1
2
3
0 0
18.3
70
1.46
48
14.7
44
5.2
58
-
-
-
-
64
38
10
30
0
o
dlVr 0
1
3. Conclusion Polymerised preformed [(N,N'-dimethyl-l,2-diphenylethane diamine)2Rh] complex allows us to obtain enantioselective material. We have then shown that it is possible to imprint an optically pure template into the rhodium-organic matrix and to use the heterogeneous catalyst in asymmetric catalysis with an obvious template effect. The study of yield versus conversion graphs has shown that the mechanism occurs via two parallel reactions on the same site without any inter-conversion of the final products. Adjusting the cross-linker ratio at 50/50 allows us to find a compromise between activity and selectivity. Phenyl ethyl ketone (propiophenone) was reduced quantitatively in 2 days to (R)-l-phenyl propanol with 70% enantiomeric excess We have then shown that the imprinting effect is obvious for molecules related in structure to the template (propiophenone, 4'-trifluoromethyl acetophenone). It is not efficient if the structure of the substrate is too different to that of the template. Further experiments using these materials and on polymers prepared without chiral monomers are under investigation. 4. REFERENCES [1] G. Wulf, Arigew. Chem. Int. Ed Engl., (1995), 34, 1812-1832. [2]
L. Fisher, R. Muller, B. Ekberg and K. Mosbach, J. Am. Chem. Soc, (1991), 113, 9358-9360.
[3]
G. Wulf and J. VietmQiQr,Makromol. Chem., (1989), 190, 1727-1735.
522 [4]
a) S. Gladiali, L. Pinna, G. Delogu, S, De Martin, G. Zassinovich and G. Mestrioni, Tetrahedron : Asymmetry, (1990), 1, 635. b) G. Zassinovich, G. Mestrioni and S. Gladiali, Chem. Rev. , (1992), 92, 1051-1069.
[5]
P. Gamez, F. Fache, P Mangeney and M. Lemaire, Tetrahedron Lett, (1993), 34, 68976898.
[6]
P. Gamez, B, Dunjic, F. Fache and M. Lemaire,./ Chem. Soc, Chem. Commitn, (1994), 1417.1418.
17]
P. Gamez, B. Dunjic, C. Pinel and M. Lemaire, Tetrahedron Lett, (1995), 36, 87798782.
[8]
ratio calculated as below : cross-linking ratio = [sum of fimctional groups from triisocyanates] I [sum of functional groups from diisocyanates]