Investigations on rhodium-catalyzed asymmetric hydroformylation Citation for published version (APA): Zijp, E. J. (2007). Investigations on rhodium-catalyzed asymmetric hydroformylation. Eindhoven: Technische Universiteit Eindhoven. https://doi.org/10.6100/IR627570 DOI: 10.6100/IR627570 Document status and date: Published: 01/01/2007 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected]providing details and we will investigate your claim. Download date: 17. Jun. 2020
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Investigations on rhodium-catalyzed asymmetrichydroformylationCitation for published version (APA):Zijp, E. J. (2007). Investigations on rhodium-catalyzed asymmetric hydroformylation. Eindhoven: TechnischeUniversiteit Eindhoven. https://doi.org/10.6100/IR627570
DOI:10.6100/IR627570
Document status and date:Published: 01/01/2007
Document Version:Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers)
Please check the document version of this publication:
• A submitted manuscript is the version of the article upon submission and before peer-review. There can beimportant differences between the submitted version and the official published version of record. Peopleinterested in the research are advised to contact the author for the final version of the publication, or visit theDOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and pagenumbers.Link to publication
General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.
• Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.
If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, pleasefollow below link for the End User Agreement:www.tue.nl/taverne
Take down policyIf you believe that this document breaches copyright please contact us at:[email protected] details and we will investigate your claim.
Investigations on Rhodium-Catalyzed Asymmetric Hydroformylation
PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de Rector Magnificus, prof.dr.ir. C.J. van Duijn, voor een commissie aangewezen door het College voor Promoties in het openbaar te verdedigen op dinsdag 3 juli 2007 om 16.00 uur door Eric Jurriën Zijp geboren te Sleeuwijk
Dit proefschrift is goedgekeurd door de promotor: prof.dr. D. Vogt Copromotor: dr. H.C.L. Abbenhuis
Investigations on Rhodium-Catalyzed Asymmetric Hydroformylation / by Eric Jurriën Zijp
Eindhoven : Eindhoven University of Technology, 2007
A catalogue record is available from the Eindhoven University of Technology Library
ISBN: 978-90-386-1055-9
Omslag: Oranje Vormgevers Eindhoven, naar een idee van Henrike Klein Ikkink
Monodentate phosphoramidites were successfully applied in asymmetric hydrogenation
of various substrates owing to their modular nature and ease of preparation allowing for
the construction of large libraries of ligands to be used in fast identification of new and
efficient catalysts. This prompted a feasibility study of these versatile compounds as
chiral ligands in the rhodium-catalyzed asymmetric hydroformylation of the benchmark
12
Chapter 1 Introduction and Scope
substrates styrene and vinyl acetate. Good activities, chemoselectivities and
regioselectivities were generally achieved. The best ee however reached only a
moderate value of 27% when ligand 19 was used.[45] The highest activities were found
when the phosphites of Whiteker and coworkers (20) were applied[46] and very high
regioselectivities (b:l = 39) were obtained with the phosphacyclic ligand (21) developed
by Clark et al.[37]
22.1 - 5% 22.2 - 14% 22.3 - 68%
O
OP N O
OP N
O
OP N
tBu
tBu
Figure 10 Phosphoramidite ligand series 22.1-22.3 with obtained ee when employed in asymmetric
hydroformylation of allyl cyanide at 60 ºC (L:Rh = 3:1) in benzene.
Best results in terms of enantioselectivity for allyl cyanide as the substrate were
obtained with the phosphoramidites 22 by Ojima and coworkers (see Figure 10).[47] In
the ligand series 22.1-22.3 the importance of the 3- and 3'-positions was once more
confirmed. Upon lowering the temperature to 25 ºC 80% ee was obtained in toluene,
although complete conversion was only reached after 74h. A solvent screening
confirmed that toluene was the best solvent among those tested (THF, dichloromethane
and MeOH).
The authors performed a molecular modelling study (Spartan; MM2/PM3) to try to
understand the dramatic effect by using the bulkiest ligand 22.3. It was shown that due
to the steric repulsion the two ligands should coordinate in the equatorial-equatorial
positions of the trigonal-bipyramidal Rh-complex.
13
Chapter 1 Introduction and Scope
1.6 Conclusions
Asymmetric hydroformylation has become a more competitive transformation for fine-
chemical industry. The development of more selective and active ligand systems,
applicable for more than a single substrate has taken a high flight. Commercially
available ligands for asymmetric hydrogenation proved to form efficient
hydroformylation catalysts under the right conditions determined by using HTE
techniques.
1.7 Perspective
There is a lot to gain by spectroscopic analysis of hydroformylation catalysts under
working conditions, which is only occasionally done so far. A better understanding of
the stereoselective step could be acquired by theoretical investigations on sufficient
high level of modelsystems of the most successful systems. Comparison of different
catalyst-systems is often difficult since experimental conditions are critical and hardly
ever identical; a comprehensive database with all available data on the asymmetric
hydroformylation reaction would prove invaluable in seeing through all quantitative
structure performance relationships.
14
Chapter 1 Introduction and Scope
1.8 Aim and Scope of Thesis
In this thesis the development of new hydroformylation catalysts is presented. Newly
synthesized ligands and their transition metal complexes were analyzed carefully via
spectroscopic means, X-ray analyses and DFT calculations. Application in asymmetric
hydrogenation and hydroformylation reactions showed the potential in catalysis. The
catalysts were monitored under working conditions to determine the coordination-
modes. The obtained data can be used for a better understanding of the reaction and the
development of new generations of catalysts.
In Chapter 2 the successful synthesis of a series of symmetrically and non-
symmetrically substituted chiral bisaminophosphine ligands following two modular
routes applying easy purification procedures is shown. X-ray analyses of both free
ligands and mononuclear cis-coordinated transition metal complexes thereof indicated
the trigonal planar geometry of the nitrogen atoms, as well as a P-N bond with double
bond character.
Chapter 3 contains DFT calculations performed on model compounds for
bisaminophosphine ligands to analyze the geometries and charge distributions. The
computed structure of a simplified cis-Pd complex of a bidentate bisaminophosphine
ligand gives valuable information on the coordination behavior. Catalysts generated in
situ from [Rh(cod)2]BF4 and bisaminophosphine ligands were used in the asymmetric
hydrogenation of methyl Z-acetylaminocinnamate with ee’s up to 91%.
The application of C2-symmetric bisaminophosphine ligands in the Rh-catalyzed
asymmetric hydroformylation of prochiral alkenes is described in Chapter 4. HP-NMR
studies indicated that equatorial - equatorial is the preferred coordination mode, which
could be confirmed by HP-IR spectroscopy.
In Chapter 5 hybrid Me-BINOLane ligands are described which form active catalysts
in the Rh-catalyzed asymmetric hydroformylation of styrene. Branched/linear ratio’s
higher than 20 were obtained. The found ee’s depend mostly on the atropisomeric
element in the phosphonite part of the ligand and reach values just over 50%.
15
Chapter 1 Introduction and Scope
1.9 References
[1] O. Roelen (to Ruhrchemie AG) German patent 849548, 1938. [2] F. Agbossou, J. -F. Carpentier, A. Mortreux, Chem. Rev. 1995, 95, 2485. [3] S. Gladiali, J. C. Bayón, C. Claver, Tetrahedron Asymmetry, 1995, 6, 1453. [4] B. Breit, W. Seiche, Synthesis, 2001, 1. [5] C. Claver, M. Diéguez, O. Pàmies, S. Castillón, Top. Organomet. Chem. 2006, 18, 35. [6] C. Claver, P. W. N. M. van Leeuwen, Rhodium Catalyzed Hydroformylation (Eds. C. Claver, P.
W. N. M. van Leeuwen), Kluwer-CMC, Dordrecht, 2000, pp 107. [7] M. L. Clarke, Curr. Org. Chem. 2005, 9, 701. [8] E. D. Daugs, W.-J. Peng, C. L. Rand (to DOW Technologies Inc.) World patent WO
2005110986 A1, 2004. [9] J. R. Briggs, J. Klosin, G. T. Whiteker, Org. Lett. 2005, 7, 4795. [10] M. C. J. Harris, M. Jackson, I. C. Lennon, J. A. Ramsden, H. Samuel, Tetrahedron Lett. 2000,
41, 3187. [11] G. Consiglio, P. Pino, Helv. Chim. Acta, 1976, 59, 642. [12] Y. Kawabata, T. M. Suzuki, I. Ogata, Chem. Lett. 1978, 4, 361. [13] P. Haelg, G. Consiglio, P. Pino, J. Organomet. Chem. 1985, 296, 281. [14] C. U. Pittmann, Y. Kawabata, L. I. Flowers, J. Chem. Soc., Chem. Commun. 1982, 473. [15] G. Parinello, R. Deschenaux, J. K. Stille, J. Org. Chem. 1986, 51, 4189. [16] G. Parinello, J. K. Stille, J. Am. Chem. Soc. 1987, 109, 7122. [17] J. K. Stille, G. Parinello (to Colorado State University Research Foundation), World Pat.
88/08835, 1988. [18] a) P. Meessen, D. Vogt, W. Keim, Organometallics, 1998, 551, 165. b) R. van Duren, Platinum
Catalyzed Hydroformylation, PhD thesis, University of Eindhoven, 2004. c) R. van Duren, L. L.
J. M. Cornelissen, J. I. van der Vlugt, J. P. J. Huijbers, A. M. Mills, A. L. Spek, C. Müller, D.
Vogt, Helv. Chim. Acta, 2006, 89, 1547. [19] L. Kollár, J. Bakos, I. Tóth, B. Heil, J. Organomet. Chem. 1988, 350, 277. [20] L. Kollár, P. Sándor, G. Szalontai, J. Mol. Cat. 1991, 67, 191. [21] C. P. Casey, S. C. Martins, M. A. Fagan, J. Am. Chem. Soc. 2004, 126, 5585. [22] J. E. Babin, G. T. Whiteker (to UCC) World Pat. 93/03839, 1993. [23] G. J. H. Buisman, E. J. Vos, P. C. J. Kamer, P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton
Trans. 1995, 409. [24] G. J. H. Buisman, P. C. J. Kamer, P. W. N. M. van Leeuwen, Tetrahedron Asymmetry, 1993, 4,
1625. [25] see for example a) M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón, C. Claver, Chem. Eur. J. 2003,
7, 3086; b) M. Diéguez, A. Ruiz, C. Claver, Dalton Trans. 2003, 2957. [26] G. J. H. Buisman, L. A. van der Veen, A. Klootwijk, W. G. J. de Lange, P. C. J. Kamer, P. W.
N. M. van Leeuwen, D. Vogt, Organometallics, 1997, 16, 2929. [27] C. J. Cobley, J. Klosin, C. Qin, G. T. Whiteker, Org. Lett. 2004, 6, 3277.
16
Chapter 1 Introduction and Scope [28] N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115, 7033. [29] N. Sakai, K. Nozaki, H. Takaya, J. Chem. Soc. Chem. Comm. 1994, 395. [30] T. Higashijima, N. Sakai, K. Nozaki, H. Takaya, Tetrahedron Lett. 1994, 35, 2033. [31] T. Horiuchi, T. Ohta, K. Nozaki, H.Takaya, Chem. Comm. 1996, 155. [32] T. Horiuchi, T. Ohta, E. Shirakawa, K. Nozaki, H.Takaya, J. Org. Chem. 1997, 62, 4285. [33] a) M. Petit, A. Mortreux, F. Petit, G. Buono, G. Pfeiffer, New. J. Chem. 1983, 7, 583. b) E.
Cesarotti, A. Chiesa, G. D’Alfonso, Tetrahedron Lett. 1982, 23, 2995. c) G. Pracejus, H.
Pracejus, J. Mol. Catal. 1984, 24, 227. [34] R. Ewalds, E. B. Eggeling, C. H. Alison, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt,
Chem. Eur. J. 2000, 6, 1496. [35] J. J. Carbó. A Lledós, D. Vogt, C. Bo, Chem. Eur. J. 2006, 12, 1457. [36] Y. Yan, X. Zhang, J. Am. Chem. Soc. 2006, 128, 7198. [37] T. P. Clark, C. R. Landis, S. L. Freed, J. Klosin, K. A. Abboud, J. Am. Chem. Soc. 2005, 127,
5040. [38] A. T. Axtell, J. Klosin, K. A. Abboud, Organometallics, 2006, 25, 5003. [39] J. Huang, E. Bunel, A. Allgeier, J. Tedrow, T. Storz, J. Preston, T. Correll, D. Manley, T.
Soukup, R. Jensen, R. Syed, G. Moniz, R. Larsen, M. Martinelli P. J. Reider [40] S. Breeden, D. J. Cole-Hamilton, D. F. Foster, G. J. Schwarz, M. Wills, Angew. Chem. Int. Ed.
2000, 39, 4106. [41] a) I. Ogata, Y. Ikeda, Chem. Lett. 1972, 487. b) M. Tanaka, Y. Watanabe, T.-A. Mitsudo, K.
Yamamoto, Y. Takegami, Chem. Lett. 1972, 483. [42] F. Lagasse, H. B. Kagan, Chem. Pharm. Bull. 2000, 48, 315. [43] J. -I. Sakaki, W. B. Schweizer, D. Seebach, Helv. Chim. Acta, 1993, 76, 2644. [44] M. T. Reetz, H. Oka, R. Goddard, Synthesis, 2003, 1809. [44] L. Panella, Phosphoramidite Ligands and Artificial Metalloenzymes in Enantioselective
Rhodium-Catalysis, PhD thesis, Rijksuniversiteit Groningen, 2006. [46] A. T. Axtell, C. J. Cobley, J. Klosin, G. T. Whiteker, A. Zanotti-Gerosa, K. A. Abboud, Angew.
Chem. Int. Ed. 2005, 44, 5834. [47] Z. Hua, V. C. Vassar, H. Choi, I. Ojima, Proc. Natl. Acad. Sci. USA, 2004, 101, 5411.
17
Chapter 2
Synthesis of Bisaminophosphine Ligands and
Their Coordination Behavior
The versatile modular synthesis of novel symmetrically and
non-symmetrically substituted bisaminophosphine ligands is
described. Investigation of the molecular structures showed the
trigonal planar geometry of the nitrogen atoms and a
significant contribution of π-bonding to the P-N bond.
Upon complexation to late transition metals mononuclear cis-
coordination was mainly found.
Chapter 2 Synthesis of Bisaminophosphine Ligands and Their Coordination Behavior
2.1 Introduction
The coordination chemistry of diphosphine ligands with a variety of transition metals
is widely studied and several types of coordination modes have been established over
the years.[1] Numerous families of novel (chiral) ligands have been synthesized,[2] with
emphasis on cis-chelating properties to form monomeric metal complexes. Besides
ligand design based on desired behavior towards transition metal complexes and the
catalytic activity of such systems, the approach of modular design and availability of
cheap resources has gained significant importance.
Especially in asymmetric catalysis such a modular approach is highly desirable, since
full understanding of the factors governing the enantioselectivity during the catalytic
cycle is often lacking and the availability of tunable ligand families would greatly
enhance the generation of data leading to new insights. We have therefore set out to
explore new chiral diamines as chiral auxiliaries, since they form a class of hitherto
neglected ligand backbones.
N
NPPh2
PPh2
N
N
H
H
PPh2
PPh2
N PN
o-An
Ph
P
P
N
N
N
N
PhPh
i
ii
iii iv
Figure 1 Aminophosphine ligand systems based on substituted heteroatoms: Piperazine (i) and 1,2-
diaminobenzene (ii), developed by the group of Woollins3 and the ligands SEMI-ESPHOS (iii) and
ESPHOS (iv) reported by Wills et al.10
The synthesis and limited use of heteroatom substituted phosphines (Figure 1) and
their transition metal complexes has received quite some attention lately,[3-5] due to
the search for new structural diversity and catalytic activities. However, little has
appeared on the use of chiral diamines as backbone structures for phosphorus ligands,
although some reports described their application in the asymmetric hydrogenation of
20
Chapter 2 Synthesis of Bisaminophosphine Ligands and Their Coordination Behavior
various substrates.[6-9] Wills et al. have described the synthesis and application of the
so-called ESPHOS ligand system iv (Figure 1) in the rhodium-catalyzed asymmetric
hydroformylation of vinylacetate, with high enantioselectivities, although commercial
availability of the chiral diamine used is limited.[10] Generally chiral amines are
widely available nowadays due to heavy industrial investments in commercially
viable synthetic intermediates and specialty chemicals. Therefore the application of
chiral amines to build up the chiral backbone could be a viable approach.
In this chapter we report on the synthesis of novel chiral bidentate aminophosphine
ligands modularly constructed from chiral amines, both symmetrically and non-
symmetrically substituted, together with a study of their coordination chemistry
towards the transition metals palladium, platinum and rhodium.
Chapter 2 Synthesis of Bisaminophosphine Ligands and Their Coordination Behavior
2.7 References [1] C. A. Bessel, P. Aggarwal, A. C. Marschilok, K. J. Takeuchi, Chem. Rev. 2001, 101, 1031. [2] For a recent review on chiral phosphorus ligands, see: W. Tang, X. Zhang, Chem. Rev. 2003,
103, 3029. [3] a) M. Rodriguez i Zubiri, M. L. Clarke, D. F. Foster, D. J. Cole-Hamilton, A. M. Z. Slawin, J.
Woollins, J. Chem. Soc., Dalton Trans. 2001, 969; b) A. M. Z. Slawin, M. Wainwright, J. D.
Woollins, J. Chem. Soc., Dalton Trans. 2002, 513. [4] a) M. S. Balakrishna, V. Sreenivasa Reddy, S. S. Krishnamurthy, J. F. Nixon, J. C. T. R.
Burckett St. Laurent, Coord. Chem. Rev. 1994, 129, 1 and references therein; b) M. S.
Balakrishna, M. G. Walawalker, J. Organomet. Chem. 2001, 628, 76. [5] M. P. Magee, H.-Q. Li, O. Morgan, W. H. Hersh, Dalton Trans. 2003, 387. [6] a) M. Fiorini, G. M. Giongo, F. Marcati, W. Marconi, J. Mol. Cat. 1976, 1, 451; b) M. Fiorini,
F. Marcati, G. M. Giongo, J. Mol. Cat. 1977/78, 3, 385; c) M. Fiorini, F. Marcati, G. M.
Giongo, J. Mol. Cat. 1978, 4, 125; d) M. Fiorini, G. M. Giongo, J. Mol. Cat. 1979, 5, 303. [7] G. Pracejus, H. Pracejus, Tetrahedron Lett. 1977, 39, 3497. [8] K. Kashiwabara, K. Hanaki, J. Fujita, Bull. Chem. Soc. Jpn. 1980, 53, 2275. [9] R. Guo, X. Li, J. Wu, W. H. Kwok, J. Chen. M. C .K. Choi, A. S. C. Chan, Tetrahedron Lett.
2002, 43, 6803. [10] a) S. Breeden, M. Wills, J. Org. Chem. 1999, 64, 9735; b) S. Breeden, D. J. Cole-Hamilton, D.
F. Foster, G. J. Schwarz, M. Wills, Angew. Chem. Int. Ed. 2000, 39, 4106; c) J. Ansell, M.
Wills, Chem. Soc. Rev. 2002, 31, 259. [11] V. M. Mastrano, L. Quintero, C. A. de Parrodi, E. Juaristi, P. J. Walsh, Tetrahedron, 2004, 60,
1781. [12] M. W. van Laren, C. J. Elsevier, Angew. Chem. Int. Ed. 1999, 38, 3715. [13] a) M. L. Clarke, A. M. Z. Slawin, J. D. Woollins, Phosphorus, Sulfur and Silicon, 2001, 169,
5; b) S. M. Aucott, M. L. Clarke, A. M. Z. Slawin, J. D. Woollins, J. Chem. Soc., Dalton
Trans. 2001, 972. [14] P. W. Dyer, J. Fawcett, M. J. Hanton, R. D. W. Kemmitt, R. Padda, N. Singh, Dalton Trans.
2003, 104. [15] S. Jeulin, S. Duprat de Paule, V. Ratovelomanana-Vidal, J. P. Genêt, N. Champion, P. Dellis,
Angew. Chem. Int. Ed. 2004, 43, 320 and references therein. [16] R. P. Pinnell, C. A. Megerle, S. L. Manatt, P. A. Kroon, J. Am. Chem. Soc. 1973, 95, 977. [17] V. D. Makhaev, Z. M. Dzhabieva, S. V. Konovalikhin, O. A. D’Yachenko, G. P. Belov,
Koord. Khim. 1996, 22, 598. [18] a) G. P. C. M. Dekker, C. J. Elsevier, K. Vrieze, P. W. N. M. van Leeuwen, Organometallics
1992, 11, 1937; b) M. A. Zuideveld, B. H. G. Swennenhuis, M. D. K. Boele, Y. Guari, G. P.
F. van Strijdonck, J. N. H. Reek, P. C. J. Kamer, K. Goubitz, J. Fraanje, M. Lutz, A. L. Spek,
P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton Trans. 2002, 2308. [19] A. D. Burrows, M. F. Mahon, M. T. Palmer, J. Chem. Soc., Dalton Trans. 2000, 1669.
49
Chapter 2 Synthesis of Bisaminophosphine Ligands and Their Coordination Behavior [20] A. M. Z. Slawin, J. D. Woollins, Q. Zhang, Inorg. Chem. Commun. 1999, 2, 386. [21] J. Bravo, C. Cativiela, J. E. Chaves, R. Navarro, E. P. Urriolabeitia, Inorg. Chem. 2003, 42,
1006. [22] C. J. Cobley, P. G. Pringle, Inorg. Chim. Acta 1997, 265, 107. [23] J. I. van der Vlugt, M. Fioroni, J. Ackerstaff, R. W. J. M. Hanssen, A. M. Mills, A. L. Spek,
A. Meetsma, H. C. L. Abbenhuis, D. Vogt, Organometallics, 2003, 22, 5697. [24] a) J. Grimblot, J. P. Bonnelle, A. Mortreux, F. Petit, Inorg. Chim. Acta 1979, 34, 29; b) J.
Grimblot, J. P. Bonnelle, C. Vaccher, A. Mortreux, F. Petit, G. Pfeiffer, J. Mol. Cat. 1980, 9,
357. [25] P. Suomalainen, S. Jääskeläinen, M. Haukka, R. H. Laitinen, J. Pursiainen, T. A. Pakkanen,
Eur. J. Inorg. Chem. 2000, 2607. [26] M. J. Atherton, K. S. Coleman, J. Fawcett, J. H. Holloway, E. G. Hope, A. Karaçar, L. A.
Peck, G. C. Saunders, J. Chem. Soc., Dalton Trans. 1995, 4029. [27] K. G. Moloy, J. L. Petersen, J. Am. Chem. Soc. 1995, 117, 7696. [28] D. R. Drew, J. R. Doyle, Inorg. Synth. 1990, 28, 346. [29] F. T. Ladipo, G. K. Anderson, Organometallics, 1994, 13, 303. [30] H. C. Clark, L. E. Manzer, J. Organomet. Chem. 1973, 59, 411. [31] H. Mimoun, J. Y. de Saint Laumer, L. Giannini, R. Scopelliti, C. Floriani, J. Am. Chem. Soc.
1999, 121, 6158. [32] L. Xueliang, Z. Suizhi, G. Hefu, Huaxue Shiji, 1994, 16, 132. [33] O. Equey, A. Alexakis, Tetrahedron Asymmetry, 2004, 15, 1069. [34] L. Weber, A. Rausch, H. B. Wartig, H. -G. Stammler, B. Neumann, Eur. J. Inorg. Chem.
2002, 2438. [35] R. P. Kamalesh Babu, S. S. Krishnamurthy, M. Nethaji, Tetrahedron Asymmetry, 1995, 6,
427. [36] S. M. Ludeman, D. L. Bartlett, G. Zon, J. Am. Chem. Soc. 1979, 44, 1163. [37] a) SADABS, Bruker AXS, Karlsruhe, Germany, 2003; b) P. T. Beurskens, G. Admiraal, G.
Beurskens, W. P. Bosman, S. García-Granda, R. O. Gould, J. M. M. Smits, C. Smykalla,
DIRDIF99 program system; University of Nijmegen, The Netherlands, 1999; c) G. M.
Sheldrick, SHELXL97; University of Göttingen, Germany, 1997. [38] A. L. Spek, J. Appl. Cryst. 2003, 36, 7.
50
Chapter 3
DFT Study into Models of
Bisaminophosphine Ligands
Application of Bisaminophosphine Ligands in
Rh-Catalyzed Asymmetric Hydrogenation
DFT calculations were performed on model compounds for
bisaminophosphine ligands to analyze the geometries and
charge distributions. The computed structure of a simplified
cis-Pd complex of a bidentate bisaminophosphine ligand gives
valuable information on the coordination behavior.
Catalysts generated in situ from [Rh(cod)2]BF4 and
bisaminophosphine ligands perform efficiently in the
asymmetric hydrogenation of (Z)-N-acetylaminocinnamate with
ee’s up to 91%. The individual contributions of
aminophosphine moieties are recognized.
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
52
MeO
AcO
COOH
NHAc
COOMe
NHAc
[Rh(cod)(DiPamp)]BF4 / H2
deprotection
HO
HO
COOH
NH2
iv v
3.1 Introduction
The demand for enantiomerically pure compounds especially for pharmaceuticals and
agrochemicals paved the way for asymmetric hydrogenation to become one of the most
studied and efficient methods to produce chiral compounds.[1] The breakthrough in this
field was initiated by Knowles and ultimately led to the discovery of the C2-symmetric
chelating compound DiPAMP (Figure 1) as a very efficient ligand the Rh-catalyzed
asymmetric hydrogenation of dehydroamino acids.[2]
PP
MeO
OMe
i ii iii
O
O
PPh2
PPh2
P
P
Figure 1 Breakthrough ligands for asymmetric hydrogenation: DiPamp (i), DIOP (ii) and DuPhos (iii).
The industrial production of L-DOPA (Parkinson’s Disease) by Monsanto emphasized
the possibility of a practical synthesis employing the developed technology (Figure
2).[3] For this work Knowles was awarded the Nobel Prize in 2001.[4] Other important
ligands in this reaction over the years are DIOP (Kagan)[5] and DuPhos (Burk).[6]
(Figure 1)
Figure 2 Monsanto’s L-DOPA (iv) process and a model substrate (v) for the asymmetric transformation.
Especially the fine chemicals industry has a strong interest in the development of new
generic classes of chiral ligands. Also in academia there is a continuing interest in this
subject aiming at deeper insight. This is reflected by the large number of publications
appearing every year. The two dedicated issues in Advanced Synthesis & Catalysis in
2003 on the subject of catalytic hydrogenation underlines this.[7]
Recently the focus shifted towards the application of monodentate ligands, mainly
phosphoramidites and phosphites (Figure 3) with a strong interest from industry due to
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
a simple synthesis.[8] Here high-throughput experimentation techniques come into play,
especially since coworkers from DSM together with the group of Feringa and the
research group of Reetz independently discovered that combinations of chiral ligands or
even the application of chiral and an additional achiral ligand could increase the
performance of individual systems significantly.[9] The number of experiments to be
performed raises exponentionally with all variables, surely if one takes into account that
each substrate has its own optimal catalytic system (ligand, metal-(precursor) and
physical conditions). A rational approach is therefore highly desirable.
O
OP O
O
OP NMe2
vi vii Figure 3 Parent monodentate BINOL-based phosphoramidite (vi) and phosphite (vii) ligands for
asymmetric hydrogenation.
Many attempts are made to quantify ligand properties and their performance in
catalysis. Two of the earliest and most famous are the quantifications of electronic
effects and steric effects by the introduction of the respective Tolman factors χ and
θ.[10] These parameters were applied to monodentate phosphorus ligands. For bidentate
phosphorus ligands the natural bite angle βn was introduced by Casey et al.[11] and
further developed by Van Leeuwen who correlated βn of series of ligands to their
performance in various homogeneously catalyzed transformations.[12] Nowadays still
high demands in computational power are required to assess ligand properties in order
to ultimately come to de novo design of ligands for a specific reaction, substrate and
regio- and stereospecifity, which still remains an elusive goal.[13]
In the late 1970’s symmetrically substituted bisaminophosphine ligands were developed
and used in the Rh-catalyzed asymmetric hydrogenation of functionalized alkenes.[14-17]
53
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
N
PEt2
N
PEt2
N N
PPh2PPh2
N NMe Me
PPh2 PPh2
MeN N
PPh2
Me
PPh2
Ph Ph
viii ix
x xi
Figure 4 PNNP ligands for Rh-catalyzed asymmetric hydrogenation.
Figure 4 shows some of the reported PNNP ligands; viii and ix would form 7-
membered rings with the stereogenic carbons outside the ring when complexed to Rh
while x and xi have the stereogenic information within this chelate ring.
Ligands viii-xi all performed distinctly different in catalysis and in order to come to a
better understanding of the catalytic system the expansion of this applied set of ligands
is desired. When the individual contributions of the two aminophosphine moieties in
the ligands could be investigated by an independent variation of the two chiral amines
used this would be a powerful additional tool. A fine attempt was made by Roucoux et
al.[18], however they only used commercially available non-symmetric diamines for
their purpose and were therefore limited in the number of variations.
In this chapter we present DFT calculations on model compounds mimicking the
studied bisaminophosphine ligands, to come to a better understanding of the relevant
electronic and geometric parameters of our system. The bisaminophosphine ligands
described in Chapter 2, both symmetrically as non-symmetrically substituted, were
applied in the asymmetric hydrogenation of methyl Z-acetylaminocinnamate.
54
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
3.2 Results
3.2.1 DFT Calculations on model compounds.
Models. Phosphines substituted with aryl and alkyl groups typically show mainly σ-
donor character. In order to compare the electronic properties of the bisaminophosphine
ligands from Chapter 2 with ordinary phosphines, we calculated the electron densities
on the phosphorus atoms of the four model compounds PPh3 (I), CH3PPh2 (II),
Ph2PN(CH3)2 (III) and Ph2P(pyrrole) (IV), depicted in Figure 5, by using DFT
methods. For computational purposes monodentate analogues were considered. This
allowed us to avoid oversimplification by the commonly used PH2-group, which has
very little relevance to the actual systems and is normally chosen for obvious
restrictions by computation time, and to use the more realistic PPh2-group instead.
Using the bidentate equivalent of III, model compound V, depicted in Figure 6, we also
investigated the corresponding complex (VI), cis-[PdCl2(V)]. Here methyl groups were
introduced on the phosphorus moieties instead of phenyl groups as a compromise
arising from computational limitations.
PPh3 CH3PPh2N
CH3 CH3
PPh2N
PPh2
I II III IV Figure 5 Model compounds I to IV as used in the DFT calculations.
NN
PMe2Me2P
CH3CH3NN
PMe2Me2P
CH3CH3
PdCl Cl
V VI
Figure 6 Illustration of model compounds V and VI (cis-[PdCl2(V)]), and the optimized structure for VI,
calculated by DFT.
Geometries. Selected geometric parameters (bond lengths and angles) obtained for the
optimized geometries of model compounds I-IV are listed in Table 1. The P-Cα,Ph
distance was constant for the complete series at 1.85 Å, while significant differences
were found for the P-N distance. In case of the aminophosphine III this bond length
55
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
was 1.73 Å, which is in good agreement with the values found for such bonds in
compounds 6 and 7 (1.68 Å, vide Chapter 2) while in the pyrrolyl-based compound IV
this bond length was calculated to be 1.76 Å. This is in close agreement with the
experimental data provided by Atwood et al.[19], being 1.71 Å. The only angle
comparable between the aforementioned models is the Cα,Ph-P-Cα,Ph’, which shows a
nearly constant value. Little differences exist between the internal angles Cα,Ph-P-CCH3
for compound II and Cα,Ph-P-N for compound III, which is due to the different
orientation of the two phenyl groups. These are reciprocally in trans position, towards
the methyl and N(CH3)2 group.
Table 1 Selected bond lengths and angles for the optimized geometries of model compounds I to IV and
a Electron Units (charge of electron is equal to -1) b Atoms considered in the Mulliken Population
analysis are in italics.
The charge on the phosphorus atoms is lowest in case of PPh3 (I), and the value
increases going along compounds II, III to IV. Therefore the introduction of a nitrogen
atom unequivocally raises the positive charge on the P atom, with a stronger effect
when the π-acidic pyrrole moiety is incorporated rather than a tertiary amine.
57
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
With respect to the palladium-complex VI there is strong indication of a nearly net -1
charge on the metal, with the P atoms bringing a +1 charge. Compound III bears
closest resemblance to the model ligand V used in compound VI. Comparing the net
charges on the free ligand with those present in the metal complex, the P atom
undergoes a dramatic change increasing the net positive charge of 0.5, while the charge
on the nitrogen atom decreases to a negative charge of -0.2. This can be interpreted as a
strong backdonation of the P atoms towards the Pd atom, especially if a net charge of -
0.2 is present on a chlorine atom.
3.2.2 Rh-catalyzed asymmetric hydrogenation of methyl Z-acetylaminocinnamate
The bisaminophosphine compounds described in Chapter 2 were employed as ligands
in the asymmetric hydrogenation of methyl (Z)-N-acetylaminocinnamate, one of the
benchmark substrates to assess the performance of a given chiral modifier in this
reaction (Eq. 1). The standard metal precursor [Rh(cod)2]BF4 was used, which during
catalysis is converted in-situ to [Rh(cod)L]BF4 while one of the cod (cyclooctadiene)
groups is lost and hydrogenated.
COOCH3
NHAc
H2
[Rh(cod)L]BF4
COOCH3
NHAc
*(1)
First the optimal solvent for our system was determined from a small set of commonly
used solvents in hydrogenation reactions, namely methanol, ethyl acetate and
dichloromethane. The novel ligand L7 (figure 7) was the ligand of choice for the
screening. Besides, for one entry an excess of ligand to metal (2.2 equiv) was used to
check if the performance would be significantly different. The obtained results under
typical conditions are summarized in Table 3.
58
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
Table 3 Initial solvent and stoichiometry screening for asymmetric hydrogenation of methyl (Z)-N-
acetylaminocinnamate results with [Rh(cod)L]BF4a
entry solvent equiv L TOF (mol mol-1 h-1)b conv (%)c ee (%)d 1 MeOH 1.1 73 100 40 (S) 2 CH2Cl2 1.1 37 100 66 (S) 3 EtOAc 1.1 31 100 85 (S) 4 EtOAc 2.2 34 100 85 (S)
a Reaction conditions: 0.011 mmol L7 (R) ; 0.01 mmol [Rh(cod)2]BF4 ; 5 mL solvent ; H2 atmosphere
1.1 bar ; T = 25 ºC; 1 mmol (Z)-N-acetylaminocinnamate. b Turn Over Frequency, average conversion of (Z)-N-acetylaminocinnamate over first hour. c Percent conversion of (Z)-N-acetylaminocinnamate after 18 h. d Enantiomeric excess determined by chiral GC, absolute configurations given in parentheses.
NNPPh2PPh2
NN
PPh2 PPh2
NN
PPh2 PPh2
NN
PPh2 PPh2OMeMeO
NN
PPh2 PPh2
NN
PPh2 PPh2
NN
PPh2 PPh2
L1 L2
L3 L4
L5 L6
NN
PPh2 PPh2
NN
PPh2 PPh2
NN
PPh2 PPh2
L7 L10
L11 L12
Figure 7 Bisaminophosphine ligands L1-L7 and L10-L12 used in asymmetric hydrogenation.
Obviously the performance of our catalytic system is greatly influenced by the solvent
used. The initial TOF is highest for MeOH, but in this solvent the ee was lowest. This
may be caused by a degree of degradation of the ligand by the protic solvent, which is
59
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
partially described by Pracejus et al.,[15] although with another Rh-precursor ([Rh(μ-Cl)
(C2H4)2]2) methanol outperforms benzene as the solvent in both stereospecifity as
activity in that study. Entries 2 and 3 show equal TOF’s for dichloromethane and ethyl
acetate but for ethyl acetate the highest ee was obtained (85%), which might be caused
by a beneficial participation of the carboxylic function of this ester. A similar run with
double the amount of ligand (entry 4) showed comparable activity and selectivity.
Independent of the solvent the major product obtained has the S configuration.
The ligands shown in figure 7 were now applied in the reaction using ethyl acetate, the
solvent in which the highest ee was obtained for ligand L7. The results are summarized
in Table 4.
Table 4 Asymmetric hydrogenation of (Z)-N-acetylaminocinnamate results with [Rh(cod)L]BF4
a
Entry Ligand L TOF (mol mol-1 h-1)b conv (%)c ee (%)d 1 L1 50 >99 85 (R) 2 L2 43 >99 85 (S) 3 L3 65 >99 85 (S) 4 L4 32 91 79 (S) 5 L5 85 >99 91 (R) 6 L6 93 >99 16 (R) 7 L7 31 >99 85 (S)
non symmetrically substituted ligands 8 L10 58 >99 35 (S) 9 L11 39 >99 84 (S) 10 L12 48 >99 0
a Reaction conditions: 0.011 mmol ligand ; 0.01 mmol [Rh(cod)2]BF4 ; 5 mL EtOAc ; H2 atmosphere 1.1
bar ; T = 25 ºC; 1 mmol (Z)-N-acetylaminocinnamate. b Turn Over Frequency, average conversion of (Z)-N-acetylaminocinnamate over first hour. c Percent conversion of (Z)-N-acetylaminocinnamate after 18 h. d Enantiomeric excess determined by chiral GC, absolute configurations given in parentheses.
The first striking observation is that all ligands but L6 perform equally well when ee is
concerned. In a small range of ee’s on average 85% ee is obtained, in any case the
major product being the enantiomer with the sign of rotation opposite of the sign of
rotation of the amine used in the synthesis of the ligand. The exception L6 gives only a
low ee of 16% (entry 5) but remarkably it is also the fastest ligand in the series with an
initial TOF of 93 on average over the first hour. Best ligand overall is L5 based on the
60
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
most crowded 1-naphthylethyl moiety, which gives a good TOF and the highest ee of
91% (entry 4).
L6 is the only ligand which does not possess an aromatic ring in the stereogenic amine
part, possibly making the phosphorus atoms less crowded and subsequently the Rh
center more open for the incoming substrate. Possibly the absence of π-π interactions
between ligand and substrate also plays a role. These differences may be the cause for
the observed highest activity for L6, although activities do not reach industrially viable
values (>500 mol mol-1 h-1) but it should be noted that the applied pressure is only 1.1
bar while in commercial processes the use of higher pressures is common practice.
C2-rpea-ppa-PPh2 (L11) is a pseudo C2-symmetric ligand and gives the highest ee for
the three non symmetrically substituted ligands. The ligand with one achiral element
(L10) fails to block one specific quadrant which you could identify in the quadrant
diagram model.[2] This model occupied and vacant quadrants indicate areas of
maximum and minimum repulsive interactions between parts of the catalyst and the
prochiral substrate. Therefore is is not surprising the ligand L10 generated limited
chiral induction.
Figure 8 31P{1H} spectra of in-situ generated [Rh(cod)(bisaminophosphine)]BF4 complexes of ligand L5
(top) and ligand L10 (bottom).
A means to investigate the electronic properties of the bisaminophosphine ligands is to
measure the NMR-spectra of the corresponding complexes to assess the chemical shifts
61
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
(δ 31P{1H} (ppm)) and the coupling constant of the Rh-P bond (1JRh-P (Hz)). This has
been done for the various ligands, including the non symmetrical ligands; the selected
data from the obtained spectra are summarized in Table 5. For illustration purposes
NMR-spectra of one symmetrical (L5) and one non-symmetrical ligand (L10) are
shown in Figure 8.
It was confirmed that the complexes derived by in-situ mixing the ligand and the metal
precursor [Rh(cod)2]BF4 in CDCl3 are the same as a complex synthesized on a larger
scale, isolated by precipitation and purified by crystallization (entry 0 vs. entry 1).
All complexes show comparable values, chemical shifts δ 31P around 84 ppm, and
coupling constants around 164 Hz. Both values are in the expected ranges for a cationic
Rh(I) complex bearing a diene and an electron-poor diphosphorus ligand. No
quantitative relationship can be deduced from these numbers.
Table 5 NMR study [Rh(cod)(bisaminophosphine)]BF4 complexes.
For the non symmetrically substituted ligands (entries 8-10) the picture changes, since
the phosphorus atoms are not equivalent anymore and coupling between the phosphorus
atoms occurs. For L10 the difference is significant (upfield shift of ca. 12 ppm for the
benzylaminophosphine moiety compared to the phenylethylaminephosphine group
(entry 8)). This proves the possibility of a new concept in designing and synthesizing
62
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
bisaminophosphine ligands with different electronic and steric properties for the two
donating groups.
3.3 Conclusions
From the DFT calculations the role of the nitrogen in P-N bond containing compounds
becomes more clear; the nitrogen increases the positive charge on the phosphorus atom,
which is indicative for a degree of π-bonding in the P-N bond. Upon complexation with
palladium the charge on P increases significantly.
The application of bisaminophosphine ligands in the Rh-catalyzed asymmetric
hydrogenation of (Z)-N-acetylaminocinnamate gives ee’s up to 91% and full conversion
under ambient conditions in the donating solvent ethyl acetate.
3.4 Perspective
The increase in computational power will enable the modeling of more realistic
compounds without concessions due to complexity. Or alternatively one may choose
higher level calculations to yet a better understanding of electronic interactions in
ligand, their transition metal complexes or even essential transformations during a
catalytic cycle.
The commercial availability of a wide range of chiral amines opens up extra
possibilities to find ligands with extraordinary effects in catalysis. The applied types of
bisaminophosphines may be used, and are being used, for various other homogeneously
catalyzed transformations; an example is the nickel-catalyzed alkylation of allylic
acetates.[21] Rhodium in combination with this type of bisaminophosphine ligands is
also effective in the asymmetric hydrogenation of activated ketones[18] The new
symmetrical and non symmetrical substituted bisaminophosphines reported here can
contribute to a better insight into and performance of these reactions, since their
modular and easy construction allows for ligand fine tuning in an automated synthesis
and testing setup.
63
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
3.5 Acknowledgements
Avantium Technologies is kindly acknowledged for financial support, Umicor Co is
thanked for the generous loan of precious metals. All DFT calculations were performed
by Marco Fioroni. We are indebted to Ton Staring for valuable technical assistance.
3.6 Experimental Section
General
All manipulations were carried out under argon using standard Schlenk techniques.
Chemicals were purchased from Acros, Aldrich, Lancaster or VWR and used as
received or distilled from CaH2 before use. Solvents were either taken HPLC-grade
from an argon-flushed column, packed with aluminum oxide, or distilled under argon
prior to use over an appropriate drying agent. NMR spectra were recorded at room
temperature on a Varian Mercury 400 MHz spectrometer. Chemical shifts are given in
ppm and spectra are referenced to CDCl3 (1H) or 85% H3PO4 (31P{1H}). All described
ligands were prepared following procedures described in Chapter two. (Z)-N-
acetylaminocinnamate was kindly synthesized by Gabriela Ionescu.[22] [Rh(cod)2]BF4
was synthesized following literature procedures[23] and kept under Ar.
Hydrogenation of (Z)-N-acetylaminocinnamate
A Schlenk tube was charged with 1 mmol substrate ((Z)-N-acetylaminocinnamate),
0.01 mmol catalyst precursor [Rh(cod)2]BF4 and ligand (0.011mmol) in 5 mL of the
appropriate solvent. After three H2 purges the reaction mixture was stirred at 298 K
under a constant H2 atmosphere (1.1 bar). Samples were taken under an outflow of H2
gas. The conversion was determined on a 50 m PONA (HP) column (carrier gas 150
kPa He, FID detector). For the ee measurement an L-Chiralsil Val column (carrier gas
120 kPa He, FID detector) was used.
NMR studies on [Rh(cod)(bisaminophosphine)]BF4 complexes
[Rh(cod)2]BF4 (4.0 mg, 9.9 µmol) and 1.0 equiv of the appropriate ligand were stirred
in 0.6 mL of CDCl3 at room temperature for 30 min. The solution was transferred to an
NMR tube and the locked 31P NMR spectrum was recorded.
64
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation
Computational Methods
For all the presented calculations, the Gaussian98 series of computer programs have
been used.[24]
Density Functional Methods
Standard computational methods based on the Density Functional Theory (DFT) have
been employed.[25] The used functional is the three-parameter exchange functional of
Becke[26] together with the correlation functional of Lee, Yang and Parr (B3LYP).[27]
For the P, C, Cl and H atoms the basis set used is the Pople style basis set 6-31G[28]
with diffuse (+) s- and p- functions added on the heavy atoms[29] and polarization
function[30] (d, p), adding one d function on the heavy atoms and one p function on the
hydrogens [6-31+G(d, p)]. For the transition metal palladium, the LanL2DZ Hay-Wadt
relativistic small-core effective core potential (ECP) and the corresponding basis set,
split valence double-ζ, were used.
The geometries of all the model compounds have been fully optimized using analytical
gradients technique at the B3LYP level of theory previously cited. No symmetry
constraints have been introduced. The optimized stationary points have been confirmed
through an harmonic vibrational analysis (B3LYP level), using analytical or numerical
differentiation of the obtained analytical energy first derivative. Energy calculations
were performed at the same level of the geometry optimization, including the zero-
point vibrational energy correction, applying the harmonic oscillator approximation.
65
Chapter 3 DFT Study into Models of Bisaminophosphine Ligands
3.7 References
[1] W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029 and references therein. [2] a) B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, O. J. Weinkauff. J. Am.
Chem. Soc. 1977, 99, 5946. b) W. S. Knowles, Acc. Chem. Res. 1983, 16, 106. [3] W. S. Knowles, J. Chem. Educ. 1986, 63, 222. [4] W. S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998. [5] H. B. Kagan, Chem. Commun. 1971, 481. [6] W. A. Nugent, T. V. RajanBabu, M. J. Burk, Science, 1993, 259, 479. [7] various authors, Adv. Synth. Catal. 2003, issues 1-2. [8] see for example a) M. v. d. Berg, A. J. Minnaard, R. M. Haak, M. Leeman, E. P. Schudde, A.
Meetsma, B. L. Feringa, A. H. M. de Vries, C. E. P. Maljaars, C. E. Willans, D. Hyett, J. A. F.
Boogers, H. J. W. Hendrickx, J. G. van de Vries, Adv. Synth. Catal. 2003, 345, 308. b) M. T.
Reetz, J.-A. Ma, R. Goddard, Angew. Chem. Int. Ed. 2005, 44, 2962. [9] a) D. Peña, A. J. Minnaard, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, B. L. Feringa,
Org. Biomol. Chem. 2003, 1, 1087. b) M. T. Reetz, T. Sell, A. Meiswinkel, G. Mehler, Angew.
Chem. Int. Ed. 2003, 42, 790. [10] a) C. A. Tolman, J. Am. Chem. Soc. 1970, 92, 2953; b) C. A. Tolman, J. Am. Chem. Soc. 1970,
92, 2956 ; c) C. A. Tolman, Chem. Rev. 1977, 77, 313. [11] C. P. Casey, G. T. Whiteker, Israel J. Chem. 1990, 30, 299. [12] P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100,
2741 and references therein. [13] MM/SEQM: K. D. Cooney, T. R. Cundari, N. W. Hoffman, K. A. Pittard, M. D. Temple, Y.
Zhao, J. Am. Chem. Soc. 2003, 125, 4318; AMS model: K. Angermund, W. Baumann, E.
Dinjus, R. Fornika, H. Görls, M. Kessler, C. Krüger, W. Leitner, F. Lutz, Chem. Eur. J. 1997, 3,
755; DFT: S. A. Decker, Organometallics, 2001, 20, 2827 and F. Delbecq, V. Guiral, P. Sautet,
Eur. J. Org. Chem. 2003, 2092. [14] a) M. Fiorini, G. M. Giongo, F. Marcati, W. Marconi, J. Mol. Cat. 1976, 1, 451; b) M. Fiorini,
F. Marcati, G. M. Giongo, J. Mol. Cat. 1978, 3, 385; c) M. Fiorini, F. Marcati, G. M. Giongo, J.
Mol. Cat. 1978, 4, 125; d) M. Fiorini, G. M. Giongo, J. Mol. Cat. 1979, 5, 303. [15] G. Pracejus, H. Pracejus, Tetrahedron Lett. 1977, 39, 3497. [16] K. Kashiwabara, K. Hanaki, J. Fujita, Bull. Chem. Soc. Jpn. 1980, 53, 2275. [17] R. Guo, X. Li, J. Wu, W. H. Kwok, J. Chen. M. C. K. Choi, A. S. C. Chan, Tetrahedron Lett.
2002, 43, 6803. [18] A. Roucoux, I. Suisse, M. Devocelle, J.-F. Carpentier, F. Agbossou, A. Mortreux, Tetrahedron:
Asymmetry, 1996, 7, 379. [19] J. L. Atwood, A. H. Cowley, W. E. Hunter, S. K. Mehrotra, Inorg. Chem. 1982, 21, 1354. [20] R. S. Mulliken, J. Chem. Phys. 1955, 23, 1833. [21] H. Bricout, J.-F. Carpentier, A. Mortreux, Tetrahedron Lett. 1996, 37, 6105. [22] S. Gladiali, L. Pinna, Tetrahedron Asymmetry, 1991, 2, 623.
66
Chapter 3 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydrogenation [23] T. G. Schenck, J. M. Downes, C. R. C. Milne, P. B. Mackenzie, H. Boucher, J. Whelan, B.
Bosnich, Inorg. Chem. 1985, 24, 2334. [24] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G.
Zakrzewski, J. A. Montgomery Jr., R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A.
D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B.
Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q.
Cui, K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J.
Cioslowski, J. V. Ortiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.
Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C.
Gonzalez, M. Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres,
M. Head-Gordon, E. S. Replogle, J. A. Pople, Gaussian 98, Revision A.3 (by Gaussian, Inc.),
1998, Pittsburgh. [25] R. G. Parr, W. Yang, in Density Functional Theory of Atoms and Molecules, R. G. Parr, and W.
Yang, (Eds.): Oxford Science Publications, 1989, Oxford. [26] A. D. Becke, J. Chem. Phys. 1993, 95, 5648. [27] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785. [28] W. J. Hehre, R. Ditchfield, J. A. Pople, J. Chem. Phys. 1972, 56, 2257. [29] M. J. Frisch, J. A. Pople, J. S. Binkley, J. Chem. Phys. 1984, 80, 3265. [30] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem. Phys. 1980, 72, 650.
67
Chapter 4
Application of Bisaminophosphine Ligands in
Rh-Catalyzed Asymmetric Hydroformylation
C2-symmetric bisaminophosphine ligands were applied in the
Rh-catalyzed asymmetric hydroformylation of prochiral
alkenes. For styrene the branched/linear ratio reached 12, the
ee remained limited to 12%. Vinyl acetate was hydroformylated
more efficiently: the desired branched product was observed in
high selectivity with a branched/linear ratio up to 50. The ee’s
were medium with a maximum of 51%. HP-NMR studies
indicated that equatorial - equatorial is the preferred
coordination mode, which could be confirmed by HP-IR
spectroscopy.
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
70
R R
CHO
RCHO+
branched linear
CO/H2
cat. *
4.1 Introduction
Hydroformylation or oxo-synthesis is the atom-efficient process in which an aldehyde
is produced from an alkene via the catalyzed addition of carbon monoxide and
dihydrogen (Eq. 1).
(1)
Propene is the most important substrate in industrial applications, since annually bulk
amounts of n-butanal are converted among others to plasticizer alcohols for the
polymer industry.[1-3] The regioselectivity is here a very important parameter; the linear
aldehyde being the desired product.[4]
The branched product is desired in the asymmetric hydroformylation of prochiral
substrates, here the carbon skeleton of an alkene is extended by one carbon atom and a
stereocenter is created. The thus formed optically active aldehydes are of high synthetic
utility in organic synthesis.[5] These chiral molecules, in enantiomerically pure form, are
valuable precursors for drugs, agrochemicals and food additives.[4] An example lies in
the asymmetric hydroformylation of allyl cyanide described by De Vries et al.[6] The
product 2-methyl-3-cyanopropanal can be converted by a hydrogenation step to 3-
methyl-4-aminobutanol which is used as a building block for a new Tachykinin NK1
receptor antagonist[7]
A real breakthrough occurred in this field with the discovery of the Rh/BINAPHOS (i)
catalyst systems by Takaya et al.[8] Since then, new active chiral ligands such as
aminophosphine phosphinites (ii)[9] and diphosphites (iii)[10,11] have been developed,
see figure 1. Also Pt/Sn-based systems were considered and successfully applied.[12]
However, hydroformylation has yet not been used in organic synthesis on a frequent
basis. Simultaneous control of regio- and enantioselectivity, while maintaining
sufficient activity is the big challenge to be addressed.
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
O
O
PO
PPh2
O
MeN
Ar2PPh
Me
PPh
R
i ii
OOPP
O
O
tBu
tBu
O
O
tBu
tBu
R
R
R
R
P
O
O
tBu
tBu
R
R
OO
OP
O
O
tBu
tBu
R
R
O
iii iv Figure 1 Ligands for asymmetric hydroformylation: BINAPHOS (i), AMPP (ii), diphosphites (iii, iv).
Recently progress has been made in the field with the development of new chiral
AMPP (aminophosphine phosphonite) ii ligands in the group of Vogt.[9] Although the
BINAPHOS system remains the benchmark catalyst in asymmetric hydroformylation,
the AMPP ligand family provides enormous potential for variation and ligand fine-
tuning. A very recent theoretical investigation by Carbó et al. gave more insight in
these systems and will potentially lead to more successful ligands in due time.[13] Sugar
based diphosphites (e.g. iv) give a tremendous number of successful ligands from the
chiral pool.[11]
All ligands which provide high enantioselectivities have one common characteristic:
the ligands coordinate in the hydrido rhodium complexes in a specific mode. Either in
the equatorial/equatorial (ee) manner (diphosphites) or the equatorial/axial (ea) manner
(BINAPHOS/AMPP) in the trigonal bipyramidal.[14] In the latter cases the stronger π-
acceptor phosphorus atom occupies the axial position, trans to the hydride, while the
equatorial position of the complex is occupied by the stronger σ-donor phosphorus
atom.
71
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
Rh CO
H
CO
P
P PP
Rh CO
HOC
ee ea
Rh RhCO
PPP
P
OC
CO
CO
Scheme 1 Equatorial/equatorial ee and equatorial/axial ea coordination modes in trigonal bipyramidal
The 31P{1H} spectra show a doublet at around 88 ppm with a 1JRh-P (Hz) coupling of
around 145 Hz. This seems to indicate that the two phosphorus atoms are magnetically
equivalent and therefore coordinate predominantly in the equatorial - equatorial
coordination mode, although the complexes are dynamic. Figure 4 shows the 31P{1H}-
NMR spectrum of the representative catalyst system based on ligand L7.
ppm
Figure 4 31P{1H}-NMR spectrum of the representative catalyst system based on ligand L7.
76
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
In the hydride region a clear doublet of triplets was visible around –9 ppm for all
ligands with a C2 bridge but L5, vide infra. Figure 5 shows the 1H-NMR spectrum in
the hydride region of the representative ligand L7.
ppm
Figure 5 1H-NMR spectrum of the hydride region of the representative catalyst system based on ligand
L7.
The values of 1J Rh-H range from 5.5 to 9.1 Hz and the 2J P-H coupling constants vary
between 11.9 and 16.8 Hz. These numbers do not give a clear indication weather the
seemingly obvious equatorial - equatorial coordination mode is the major or the only
species in solution, since it is known that the species may interchange on the NMR
timescale giving rise to average coupling constants.
Ligand L5 based on 1-naphthyl has a distinctly different appearance in 1H NMR. From
NMR simulation it could be deduced that the 1J Rh-H and the 2J P-H differ that little in
magnitude (5.5 Hz vs. 6.8 Hz) in this catalyst system that the signal appears as a pseudo
quartet. Also from these coupling constants it is obvious that L5 coordinates
predominantly in the equatorial - equatorial mode. An equatorial - axial relationship
would lead to larger values for the found coupling constants as found for related
diphosphite systems.[18] No indication is found that bridged species (Scheme 1) exist
under these (concentrated) conditions and therefore are also thought to be absent during
the hydroformylation experiments.[19]
77
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
The only measured ligand with a C3 bridge, L8, surprisingly only shows a doublet in
the hydride region, which could imply fast exchange of the phosphorus atoms. The 31P{1H}-NMR spectrum gives a doublet more downfield than for the other ligands in
this series and the 1JRh-P coupling is significantly larger. This could indeed indicate a
larger contribution of ea coordinated species in solution.
To validate the assumption that after releasing pressure the obtained complexes in
solution are stable enough to be measured in the way described above the 1H-NMR
spectrum of the ligand L5 were also measured in the 10 mm sapphire NMR tube after
the same preformation on a Bruker 200 MHz under pressure. Figure 6 shows the
obtained spectrum (hydride region).
-8.4 -8.8 -9.2 -9.6 ppm
Figure 6 1H-NMR spectrum of L5 / Rh(acac)(CO)2 catalyst system under syngas conditions (hydride
region).
The measured chemical shifts and coupling constants were identical to the values
obtained for the system after releasing pressure. We believe that analogously the other
catalyst systems would show equal behavior and therefore that the comparison of
spectral parameters is justified.
The preformation of the catalyst complex is also followed over time at room
temperature under 20 bar syngas (1:1 CO/H2) pressure, see figure 7. The first spectrum
is taken after 21 minutes. After 7h the doublet of triplets pattern is already visible.
Every 7 hours another spectrum is recorded and it shows that after 42 hours the
preformation is complete. Compared to the preformation at 60°C no spectral
differences exist, only the rate of the reaction (full conversion in less than one hour) is
as expected slower. Note that the preformation conditions in the latter experiments are
equal to the conditions applied during the hydroformylation experiments, besides the
higher concentrations for the sake of sensitivity of the spectrometer. This confirms that
78
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
the 1 hour preformation time during regular hydroformylation experiments is likely to
be sufficient for a full transformation to the catalytic resting state.
56 h 49 h 42 h 35 h 28 h 21 h 14 h 7 h 21 min
δ (ppm)
Figure 7 HP-NMR of the L5 / Rh(acac)(CO)2 catalyst system followed over time, hydride region.
4.2.3 HP-IR
For additional information on the coordination behavior close to reaction conditions,
with regard to catalyst concentration and pressure, HP-IR is used. The ligand is
dissolved in cyclohexane and stirred with one equivalent of Rh(acac)(CO)2. The
solution is transferred to an autoclave equipped with IR-transparent windows (ZnS) and
a dedicated FT-IR machine where it is pressurized to 20 bar syngas (1:1 H2/CO) at 60
°C. The observed signals in the carbonyl stretching region are listed in Table 4. It is
apparent that for the measured C2 bridged ligands L2 and L5 there is only one complex
present in solution with equatorial – equatorial coordinated ligand since two bands
with equal intensities are found. This is similar to the findings of van der Vlugt et al.[20]
with sterically constrained diphosphonites, while with Xantphos type ligands mixtures
of ee and ea coordinated species are obtained which are in fast equilibrium, which is
reported by van der Veen et al. [21]
79
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
Table 4 Selected HP-IR data of the νCO on preformed Rh(acac)(CO)2 catalyst systems
Caution! The hydroformylation experiments are performed with syngas (1:1 = CO/H2)
which is extremely poisonous. Accidents may be lethal. When working with carbon
monoxide a sensitive personal detector should be carried and all experiments are to be
performed in a well ventilated fumehood equipped with a detector, maintaining the CO
concentration in the fumehood below the MAC-value.
Hydroformylation of styrene
Hydroformylation experiments were carried out in home made 75 mL stainless steel
autoclaves, equipped with a glass inner beaker and a magnetic stirrer. The temperature
was controlled by an internal thermocouple. In a typical hydroformylation experiment
the autoclave was heated up to 60 °C and dried under vacuum for 1 h. After cooling the
catalyst precursor (13.1 μmol in 5 mL toluene) is introduced by syringe, rinsing the
Schlenk tube with an additional 5 mL solvent. Likewise the appropriate ligand (26.2
μmol) is added after which the autoclave is purged with syngas, pressurized to 20 bar
and heated to the reaction temperature for the duration of the preformation time (1 h).
82
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
Then a freshly prepared stock solution of styrene ((2.0 mL, 17.4 mmol) filtered over
neutral, activated alumina), internal standard n-decane (1.0 mL, 5.1 mmol) and 5 mL
toluene was added under pressure. The total mixture was allowed to react for 15 h. The
autoclave was then cooled, depressurized and vented with argon. The reaction mixture
was transferred and distilled quantitatively to remove catalyst and excess of ligand. A
sample was analyzed for conversion and regioselectivity. For the ee determination a
part of the mixture was dropped into a suspension of LiAlH4 in Et2O and after 1 h
quenched with water. The mixture was extracted and dried over NaSO4 and evaporated
to dryness under reduced pressure. The residue was dissolved in CH2Cl2 and treated
with 2 equiv of trifluoro acetic acid anhydride. After evaporation to dryness under
reduced pressure a sample of the resulting trifluoro acetate (20 μL) was dissolved in
CH2Cl2 and analyzed by chiral GC.
Hydroformylation of vinyl acetate
A similar procedure as for the hydroformylation of styrene was used. Vinyl acetate (1.5
mL, 16.3 mmol), internal standard ethyl propionate (0.5 g, 4.9 mmol) and benzene as
solvent were applied. After the catalytic experiment the reaction mixture was distilled
under vacuum in order to remove catalyst and excess of ligand. The composition of the
mixture was measured directly by GC without further workup.
HP-NMR experiments
A 10mm outer diameter sapphire NMR tube was filled with a solution of
Rh(acac)(CO)2 (5.0 mg, 19.4 mmol), 1.1 equiv ligand ((21.3 mmol) small excess for
referencing to free ligand) and toluene-d8 (1.5 mL). The tube was purged three times
with syngas and pressurized to 20 bar. The tube was then brought to the desired
temperature and spectra were recorded over time.
HP-IR experiments
The autoclave was flushed with argon for at least an hour. Then a solution of
Rh(acac)(CO)2 (4.9 mg, 19 mmol) and ligand (20 mmol) in 15 mL cyclohexane were
introduced under argon outflow. The equipment was flushed three times with syngas
and afterwards brought to the desired temperature and syngas pressure. Spectra were
recorded after 1 hour preformation.
83
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
4.7 References
[1] D. Selent, K. D. Wiese, D. Rotger, A. Börner, Angew. Chem. Int. Ed. 2000, 39, 1639. [2] C. D. Frohning, C. W. Kohlpaintner, Applied Homogeneous Catalysis with Organometallic
Compounds, Vol 1, Wiley-VCH, Weinhein, 1996, 3. [3] W. A. Herrmann, B. Cornils, Angew. Chem, 1997, 109, 1074. [4] a) B. Cornils, W. A. Herrmann, Ed., Applied Homogeneous Catalysis with Organometallic
Compounds, Vol 1, Wiley-VCH, Weinhein, 2002, 31; b) P. W. N. M. van Leeuwen, C. Claver,
Ed., Rhodium Catalyzed Hydroformylation, Kluwer-CMC, Dordrecht, 2001. [5] a) F. Agbossou, J. -F. Carpentier, A. Mortreux, Chem. Rev. 1995, 95, 2485; b) B. Breit, W.
Seiche, Synthesis, 2001, 1. [6] J. G. de Vries, M. M. H. Lambers-Verstappen, Adv. Synth. Catal, 2003, 345, 478. [7] a) H. Natsugari, Y. Ikeura, I. Kamo, T. Ishimaru, Y. Ischichi, A. Fujishima, T. Tanaka, F.
Kasahara, M. Kawada, T. Doi, J. Med. Chem, 1999, 42, 3982; b) Y. Ikeura, T. Ishimaru, T. Doi,
M. Kawada, A. Fujishima, H. Natsugari, Chem. Commun. 1998, 2141. [8] N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115, 7033. [9] R. Ewalds, E. B. Eggeling, C. H. Alison, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt,
Chem. Eur. J. 2000, 6, 1496. [10] a) J. E. Babin, G. T. Whiteker, WO 93/03830, 1992. b) G. J. H. Buisman, L. A. van der Veen,
A. Klootwijk, W. G. J. de Lange, P. C. J. Kamer, P. W. N. M. van Leeuwen, Organometallics,
1997, 16, 2929. [11] M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón, C. Claver, Chem. Eur. J. 2003, 7, 3086. [12] a) J. K. Stille, H. Su, P. Brechot, G. Parinello, L. S. Hegedus, Organometallics, 1991, 10, 1183;
b) R. van Duren, Platinum Catalyzed Hydroformylation, PhD thesis, Eindhoven University of
Technology, 2004. [13] J. J. Carbó, A. Lledós, D. Vogt, C. Bo, Chem. Eur. J. 2006, 12, 1457. [14] R. Ewalds, Asymmetrische Hydroformylierung mit Phosphor-chiralen Aminophosphin
phosphinit-Liganden, PhD thesis, RWTH Aachen, 1997. [15] a) S. Breeden, M. Wills, J. Org. Chem. 1999, 64, 9735; b) S. Breeden, D. J. Cole-Hamilton, D.
F. Foster, G. J. Schwarz, M. Wills, Angew. Chem. Int. Ed. 2000, 39, 4106; c) J. Ansell, M.
Wills, Chem. Soc. Rev. 2002, 31, 259. [16] T. J. Kwok, D. J. Wink, Organometallics, 1993, 12, 1954. [17] C. F. Hobbs, W. S. Knowles, J. Org. Chem. 1981, 46, 4422. [18] a) C. B. Dieleman, P. C. J. Kamer, J. N. H. Reek, P. W. N. M. van Leeuwen, Helv. Chim. Acta,
2001, 84, 3269; b) G. J. H. Buisman, L. A. van der Veen, P. C. J. Kamer, P. W. N. M. van
Leeuwen, Organometallics, 1997, 16, 5681. [19] A. Castellanos-Páez, S. Castillón, C. Claver, P. W. N. M. van Leeuwen, W. G. J. de Lange,
Organometallics, 1998, 17, 2543. [20] J. I. van der Vlugt, R. Sablong, P. C. M. M. Magusin, A. M. Mills, A. L. Spek, D. Vogt,
Organometallics, 2004, 23, 3177.
84
Chapter 4 Application of Bisaminophosphine Ligands in Rh-Catalyzed Asymmetric Hydroformylation
[21] L. A. van der Veen, P. H. Keeven, G. C. Schoenmaker, J. N. H. Reek, P. C. J. Kamer, P. W. N.
M. van Leeuwen, M. Lutz, A. L. Spek, Organometallics, 2000, 19, 872. [22] A. van Rooy, Rhodium Catalysed Hydroformylation with Bulky Phosphites as Modifying
Ligands, PhD thesis, Universiteit van Amsterdam, 1995.
85
Chapter 5
Phosphonite-Phospholane Ligands Applied in
Rh-Catalyzed Asymmetric Hydroformylation
Mixed phosphonite-phospholane ligands are effective when
applied in Rh-catalyzed asymmetric hydroformylation of
styrene. Branched/linear ratio’s higher than 20 were obtained
while the ee reached a moderate 55%. The dependence of the
ligand performance on pressure, temperature, and ligand
concentration was studied. NMR studies did not reveal the
coordination mode of the ligands in the trigonal bipyramidal
resting state of the catalytic cycle.
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
5.1 Introduction
The discovery and development of new successful ligands for asymmetric
homogeneous catalysts is usually a very tedious process most of the time only governed
by rules of thumb and accompanied by a lot of trial and error. However, a huge variety
of chiral ligands has been developed for certain reactions, e.g. for hydrogenation or
allylic substitution, that have never been tested for other catalytic transformations. The
potential of this existing pool of chiral ligands should not be underestimated although
results might come as a surprise, valuable new insight might be generated. Interesting
results on asymmetric hydroformylation were reported very recently by Abboud et al.
applying phosphacyclic ligands that were developed for asymmetric hydrogenations.[1]
A similar approach was followed in this study, applying phosphonite-phospholane
ligands in the Rh-catalyzed asymmetric hydroformylation of styrene.
In a joint effort of CIBA SC and A. Salzer at RWTH Aachen, a flexible approach to the
synthesis of different families of bidentate phosphorus ligands was followed for
application in asymmetric catalysis. The asymmetric hydrogenation of dehydration acid
derivatives, enamides, and itaconates proceeded with ee values of up to 98.7 %.[2]
Evaluating the structure of the mixed phosphonite-phospholanes (see Figure 1) in that
study revealed attractive features which often proved to be valuable if applied in
asymmetric hydroformylation of alkenes: The ligands consist of a rigid ligand scaffold
with mixed phosphorus functionalities expected to allow for a predominant ea
configuration of the ligand in the trigonal bipyramidal resting state of the catalyst.
Besides this the stereogenic information is close to the phosphorus for the phospholane
part[3] and the generally very effective atropisomeric bisnaphthol[4] is included in the
phosphonite moiety of the ligand.
Those observations prompted us to apply the ligands in the asymmetric
hydroformylation of styrene. Chapter 1 of this thesis contains an introduction to the
field of asymmetric hydroformylation, including description of the successful ligands,
studies into the mechanism of stereoselection and possible applications in real-life
chemistry.
88
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
89
O
OP
S
P
O
OP
S
P
I II Figure 1 Applied BINOLane ligands I and II.
Here we present the successful application of the BINOLane ligands in the asymmetric
hydroformylation of styrene. Investigations of the coordination mode of the ligands in
the trigonal bipyramidal resting state of the catalyst were undertaken.
5.2 Results
5.2.1 Catalysis
Styrene, being a generally accepted and widely used benchmark substrate for the
asymmetric hydroformylation reaction, was selected as the substrate (see Eq. 1).
CO/H2
Rh/L2
CHO
CHO
+*
(1)
The catalysts were prepared for this thorough screening by in situ mixing the ligands
with the metal precursor Rh(acac)(CO)2 in a ratio 2:1 and heating in a AMTEC SPR16
reactor under typical reaction conditions (60°C, 20 bar (1:1 CO/H2)) for 1 hour.
Subsequently the substrate with internal standard was injected and the mixture was
allowed to react under the indicated reaction conditions while measuring the gas
uptake. After workup the product distribution was analyzed by (chiral) GC directly or,
alternatively, after derivatization to the trifluoro acetic ester. Both methods gave
identical values for the ee. The results of the first screening are presented below (Table
1).
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
Table 1 Selected results of initial ligand screening under standard conditions.a
Ligand Conversion b b/l c ee (%) d I 100 21 31 (S) II 27 21 37 (R)
a Reaction conditions: T = 60 °C; p = 20 bar (1:1 CO/H2); solvent: 4 mL toluene; 2 mL styrene, 1 mL
decane internal standard; 14.3 μmol Rh(acac)(CO)2; L:Rh = 2; preformation t = 1h; reaction t = 24h. b
Percent conversion of styrene after 24h c Branched / linear ratio. d Enantiomeric excess determined by
chiral GC.
The catalyst based on BINOLane I, with the (R) enantiomer of BINOL in the
phosphonite moiety, gives full conversion of styrene in the applied time. The
branched/linear ratio is excellent with 21 and a reasonable ee of 31% is reached. With
BINOLane II, with an opposite configuration of the BINOL part of the ligand, the
conversion after 24 hours is still low and the branched/linear ratio is also 21. The
obtained branched/linear ratios can compete with the numbers obtained for settled
hybrid ligands like AMPP (20-40) [5] and BINAPHOS (7-12).[4a] The ee values of the
styrene hydroformylation products induced by the BINOLane ligands however, are
moderate compared to the renowned ligands AMPP (46%-75%)and BINAPHOS (85%-
94%).
It seems that the absolute configuration of the BINOL moiety determines the absolute
configuration of the major product. The stereogenic centers of the phospholane ring
form an inefficient matched or miss-matched pair in terms of enantioselectivity.
To determine the stability of the catalyst we followed the reaction over time by taking
samples on predetermined times, while measuring the gas uptake. The samples were
analyzed on b/l ratio and enantioselectivity (see Table 2 for details and Figure 2 for a
graphic representation).
90
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
91
0 5 10 15
0
50
100
150
200
250
Gas
upt
ake
(mL)
0
10
30
40
20
Gas uptake ee (R) b/l
Table 2 b/l ratio’s and ee’s followed over time for the respective ligands (R,R)-Me-BINOLane (I) and
(S,R)-Me-BINOLane (II).a
time (h) b/l (I) b ee (S) (I) (%) c b/l (II) b ee (R) (II) (%) c 0,37 22,8 32 19,2 38 0,71 23,5 32 19,6 36 1,04 23,9 32 19,6 35 1,87 24,6 31 20,4 36 3,21 24,8 33 20,2 37 5,21 24,3 33 20,9 36 9,55 23,0 33 21,5 37 15,3 22,6 33 21,8 38
a Reaction conditions: T = 60 °C; p = 20 bar (1:1 CO/H2); solvent: 4 mL toluene; 2 mL styrene, 1 mL
decane internal standard; 14.3 μmol Rh(acac)(CO)2; L:Rh = 2; preformation t = 1h; reaction t = 16h; 100
μL samples taken over time b Branched / linear ratio c Enantiomeric excess determined by chiral GC.
Figure 2a) upper and 2b) lower. Gas uptake, b/l ratio and ee followed over time for the respective
ligands (R,R)-Me-BINOLane (I) and (S,R)-Me-BINOLane (II).
0 5 10 150
100
200
300
400
500
600
700 Gas uptake ee (S) b/l
Time (h)
Gas
upt
ake
(mL)
0
25
50
75
100
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
For both ligands I and II the ee’s are virtually constant. The b/l ratio’s seem to increase
slowly over time, maybe dropping marginally when the conversion is full (at extended
reaction times for ligand I). This indicates that the catalyst is stable over time, but the
preformation time could be extended (or the reaction conditions during preformation
intensified) to ensure full conversion to the catalyst resting state prior to substrate
injection.
To assess the dependencies of the performance of the system on applied pressure,
temperature, and stoichiometry these parameters were systematically varied.
Firstly the applied pressure was varied from 10-40 bar syngas (1:1 CO/H2). The
obtained data are gathered in Table 3 and 4.
Table 3 b/l ratio and ee obtained for different applied pressures by using ligand (R,R)-Me-BINOLane (I).a
bar conversion (%) b b/l c ee (S) d 10 100 18 26 20 100 19 30 30 99 24 33 40 99 25 32
a Reaction conditions: T = 60 °C; p = x bar (1:1 CO/H2); solvent: 4 mL toluene; 2 mL styrene, 1 mL
decane internal standard; 14.3 μmol Rh(acac)(CO)2; I:Rh = 2; preformation t = 1h; reaction t = 24h; b
Percent conversion of styrene after 24h c Branched / linear ratio d Enantiomeric excess determined by
chiral GC. Table 4 b/l ratio and ee obtained for different applied pressures by using ligand (S,R)-Me-BINOLane (II).a
bar conversion (%) b b/l c ee (R) d 10 13 18 36 20 27 21 36 30 32 22 36 40 36 22 37
a Reaction conditions: T = 60 °C; p = x bar (1:1 CO/H2); solvent: 4 mL toluene; 2 mL styrene, 1 mL
decane internal standard; 14.3 μmol Rh(acac)(CO)2; II:Rh = 2; preformation t = 1h; reaction t = 24h; b
Percent conversion of styrene after 24h c Branched / linear ratio d Enantiomeric excess determined by
chiral GC.
92
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
93
0 5 10 15 200
100
200
300
400
500
10 bar 20 bar 30 bar 40 bar
Time (h)
Gas
Upt
ake
(mL)
0
10
20
30
Conversion (%
)
Figure 3 Gas uptake followed over time for different applied pressures by using ligand (II).
For increasing syngas pressure the conversion, the ee, and the b/l ratio all seem to go
up, albeit with small numbers. This is in contrast with the AMPP ligands where a
negative influence of the pressure on the enantioselectivity was observed.[5] Coworkers
of DOW Pharma found for a range of ligands applied for styrene, allyl cyanide and
vinyl acetate that all enantioselectivities were unaffected by changing pressure. The
regioselectivity for the styrene increased with increasing pressure, where the vinyl
acetate products were obtained with a lower regioselectivity.[6]
The second investigated parameter was the reaction temperature which was varied from
25-120 ºC. Tables 5 and 6 show the selected results. During these investigations the
applied temperature during the 1h catalyst preformation was constant with 60 ºC but the
reaction times varied.
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
Table 5 b/l ratio and ee obtained for different reaction temperatures applying ligand (R,R)-Me-
BINOLane (I). a
Temperature (°C) b/l b ee (S) (%) c 25 32 32 40 32 31 60 21 31 80 12 21 100 5 3 120 3 0
a 14.3 μmol Rh(acac)(CO)2, 2 equiv I, 4 mL toluene, 2 ml styrene, 1 mL decane, p = 20 bar CO:H2 (1:1),
1h preformation b Branched / linear ratio c Enantiomeric excess determined by chiral GC.
Table 6 b/l ratio and ee obtained for different reaction temperatures applying ligand (S,R)-Me-
BINOLane (II). a
Temperature (°C) b/l b ee (R) (%) c 25 29 55 40 28 52 60 21 37 80 14 28 100 6 8 120 4 2
a 14.3 μmol Rh(acac)(CO)2, 2 equiv II, 4 mL toluene, 2 ml styrene, 1 mL decane, p = 20 bar CO:H2 (1:1),
1h preformation b Branched / linear ratio c Enantiomeric excess determined by chiral GC.
At lower temperature the selectivity of the reaction, both in terms of b/l ratio as ee were
maximum, reaching 97% selectivity of the branched product for ligand I and more than
50% enantiomeric excess for ligand II. Logically the rate of reaction is lowest in these
cases. At higher reaction temperature the undesired polymerization of styrene plays a
significant role, besides a higher degree of degradation of the catalyst under these harsh
conditions.
The last parameter that was varied was the Rh/L(I) ratio. Table 7 gives the relevant
numbers and a graphic representation is shown in Figure 4.
94
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
95
Table 7 Conversion, b/l ratio and ee obtained for several stoichiometries of ligand (R,R)-Me-BINOLane
The obtained values suggest a mononuclear cis-coordination for both complexes, as is
found for a related cationic complex described by the coworkers of CIBA SC (Figure 6,
R = ethyl).[2a]
96
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
97
S
PR R
P
R
R
Figure 6 Bisphospholane ligand by CIBA.
In a comparable manner as described in Chapter 4 for the bisaminophosphine ligands
the coordination behavior of the here used Me-BINOLane ligands was investigated to
reveal the structure of the trigonal bipyramidal resting state of the hydroformylation
catalyst. Equimolar amounts of ligand and Rh(acac)(CO)2 were dissolved in deuterated
toluene in a 10mm sapphire NMR tube and pressurized to 20 bar of syngas. After 1
hour preformation time at elevated temperature 60°C the tube was cooled to room
temperature and measured on a Bruker 200 MHz NMR machine.
Under the applied conditions however, no signal in the hydride region was obtained.
Strategies to lengthen relaxation times, to widen the spectral width, to increase
concentrations and to prolong measuring times did not result in any information on the
coordination behavior. Maybe at room temperature the coalescence is reached for a
fluxional process in the complexes, thus resulting in a non-appearing signal. No
variation in temperature was attempted.
Comparing the structure of the ligands to a bisphospholane ligand based on the same
benzo[b]thiophene scaffold (figure 6, with R = ethyl) where a bite angle of 85° P-Rh-P
is found in a cationic Rh complex the expected coordination mode in the trigonal
bipyramidal resting state of the catalyst would be equatorial-axial. In this coordination
mode the ideal 90° angle is closely resembled. The different electronic properties of the
phospholane and the phosphonite part present in the ligand used in our study could
ensure a preferential coordination and thus the respectable enantioselectivities achieved
in this study.
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
5.3 Conclusions
The Me-BINOLane ligands form active catalysts for the Rh-catalyzed asymmetric
hydroformylation of styrene and the regioselectivity for the branched product is high
with b/l ratio’s over 20. The ee’s obtained depend mostly on the atropisomeric element
in the phosphonite part of the ligand and reach values just over 50%. Application of 2
equivalents of ligand with respect to rhodium is most efficient in a compromise
between activity and enantioselectivity.
5.4 Perspective
The ee’s obtained in this study for the asymmetric hydroformylation of styrene can not
compete with the numbers obtained with a variety of other ligands reported elsewhere.
Since the coordination mode of the ligands under reaction conditions was not disclosed
it remains speculation if preferential coordination is reached. The synthetic strategy
however allows for independent variation of the ligands in both the phospholane as the
phosphonite part. Substitution on the 2- and 2’-positions of the used bisnaphthol often
creates a more stereoselective ligand, as could be the use of ethyl- or propyl-
substituents on the phospholane ring. Other substrates like vinyl acetate or allyl cyanide
could be used to check the efficacy of the ligands in their enantioselective conversion.
The presence of the sulfur heteroatom may act as a possibility to electronically modify
the backbone (e.g. by coordination to early transition metals) or as a means to anchor
the ligands to a support, thus allowing for recycling of the ligand (or catalyst).
5.5 Acknowledgements
Avantium Technologies is kindly acknowledged for financial support, Umicor Co. is
thanked for the generous loan of precious metals. CIBA SC is thanked for putting a
sample of the used ligands to our disposal and we are especially grateful to Ulrich
Berens for detailed help on the synthetic procedures. Leandra Cornelissen is
acknowledged for the blood, sweat and tears shed during the syntheses of the ligands.
Ton Staring is gratefully acknowledged for his skillful technical assistance during the
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Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
99
chromatographic analyses. And finally Christian Müller is thanked for his kind help
during the AMTEC runs.
5.6 Experimental Section
General
All manipulations were carried out under argon using standard Schlenk techniques.
Chemicals were purchased from Acros, Aldrich, Lancaster or VWR and used as
received or distilled from CaH2 before use. Syngas (CO:H2 (1:1)) was bought from
Hoekloos. Solvents were either taken HPLC-grade from an argon-flushed column,
packed with aluminum oxide, or distilled under argon prior to use over an appropriate
drying agent. The NMR spectra were recorded on a Bruker 200 MHz spectrometer. Gas
chromatographic analyses were done on a Shimadzu 17A or a Carlo Erba (Vega Serie
2) apparatus. The reaction mixtures obtained from the asymmetric hydroformylation of
styrene were analyzed on a 25 m Ultra 2 column (carrier gas 100 kPa N2, FID detector).
The enantiomeric excess in the product 2-phenylpropanal was determined after
reduction of the aldehyde and subsequent esterification to the corresponding trifluoro
acetate on a 25 m Lipodex E capillary column (carrier gas 50 kPa H2, FID detector), or
without derivatization on a Supelco Betadex column (carrier gas 60 kPa He, FID
detector).
Hydroformylation experiments
Caution! The hydroformylation experiments are performed with syngas (1:1 = CO/H2)
which is extremely poisonous. Accidents may be lethal. When working with carbon
monoxide a sensitive personal detector should be carried and all experiments are to be
performed in a well ventilated fume hood equipped with a detector, maintaining the CO
concentration in the fume hood below the MAC-value.
Hydroformylation of styrene
Hydroformylation experiments were carried out in an AMTEC SPR16 machine. Before
use the reactors were heated up to 60 °C and dried under vacuum for 1 h. After cooling
the catalyst is introduced by syringe after which the autoclaves are purged with syngas,
pressurized to 20 bar and heated to the reaction temperature for the duration of the
Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
preformation time (1 h). After cooling and lowering the pressure a freshly prepared
stock solution of styrene ((2.0 mL, 17.4 mmol) and internal standard n-decane (1.0 mL,
5.1 mmol) was added. The mixture was then brought to the desired temperature and
pressure and it was allowed to react. The autoclaves were then cooled, depressurized
and vented with argon. From the contents a sample was analyzed for conversion and
regioselectivity on a Ultra column. For the ee determination 1 mL of the mixture was
dropped into a suspension of 150 mg LiAlH4 in Et2O and after 1 h quenched with
water. The mixture was extracted and dried over NaSO4 and evaporated to dryness
under reduced pressure. The residue was dissolved in CH2Cl2 and treated with 0.5 mL
of trifluoro acetic anhydride. After evaporation to dryness under reduced pressure a
sample of the resulting trifluoro acetate (20 μL) was dissolved in CH2Cl2 and analyzed
on a Lipodex column. Alternatively the ee could be determined directly on a Supelco
Betadex column.
NMR experiments
A 10mm outer diameter sapphire NMR tube was filled with a solution of
Rh(acac)(CO)2 (5.0 mg, 19.4 mmol), 1.1 equiv ligand (21.3 mmol, small excess for
referencing to free ligand) in toluene-d8 (1.5 mL). The tube was purged three times with
syngas and pressurized to 20 bar. The tube was then brought to the desired temperature.
After 1 hour the pressure was released and the contents were quickly transferred to a 5
mm NMR tube and directly measured or analyzed on a Bruker 200 MHz NMR machine
without prior release of pressure.
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Chapter 5 Phosphonite-Phospholane Ligands Applied in Rh-Catalyzed Asymmetric Hydroformylation
101
5.7 References
[1] A. T. Axtell, J. Klosin, K. A. Abboud, Organometallics, 2006, 25, 5003. [2] a) U. Berens, U. Englert, S. Gwyser, J. Runsink, A. Salzer, Eur. J. Org. Chem. 2006, 2100; b)
U. Berens to Solvias A.G., WO 03/031456 A2. [3] e.g. Me-DuPhos; M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow, J. Am. Chem. Soc.
1993, 115, 10125.
[4] For successful applications of the bisnaphthol unit in asymmetric hydroformylation see e.g.
(R,S)-BINAPHOS a) N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115,
7033 or (R,S)-Yanphos; b) Y. Yan, X. Zhang, J. Am. Chem. Soc. 2006, 128, 7198. [5] R. Ewalds, E. B. Eggeling, C. H. Alison, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt,
Chem. Eur. J. 2000, 6, 1496. [6] A. T. Axtell, C. J. Cobley, J. Klosin, G. T. Whiteker, A. Zanotti-Gerosa, K. A. Abboud, Angew.
Chem. Int. Ed. 2005, 44, 5834. [7] M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón, C. Claver, Chem. Commun., 2000, 1607.
Summary
Summary
Investigations on Rhodium-Catalyzed Asymmetric Hydroformylation
In asymmetric metal catalysis it is of special value to have chiral ligand classes
available which allow for a straight forward and highly modular, maybe even
automated synthesis and variability of the molecular structure. From an academic point
of view this is important in order to study in detail the structure-performance relations
in order to generate basic understanding of stereoselection mechanisms and ultimately
derive at a rational design of new catalysts for a given synthetic problem. From an
industrial point of view readily available ligand libraries allow for a rapid sceening and
optimization of a catalyst for a given substrate, as especially in fine chemicals business
the given time for development is extremely short.
Theoretical insight, next to structure-performance relations, is obtained by studying the
coordination behavior of the ligands in catalytically active species by means of
structural analysis and in situ spectroscopic investigations. This can provide valuable
data for further theoretical studies on a high level.
Chapter one gives an introduction in asymmetric hydroformylation. Starting with a
historical overview and ending with the state-of-the-art ligand systems that give the
currently most active and selective catalysts. High-Throughput-Experimentation,
theoretical investigations, and spectroscopic studies are identified as the important
elements leading to success.
In Chapter two the versatile modular synthesis of novel symmetrically and non-
symmetrically substituted bisaminophosphine ligands is described. Molecular structures
of the ligands and complexes thereof revealed a trigonal planar geometry of the
nitrogen atoms bound to the phosphorus donor atom, resulting from a significant
contribution of π-bonding to the P-N bond.
103
Summary
DFT calculations were performed on model compounds for bisaminophosphine ligands
to analyze the geometries and charge distributions, which are discussed in Chapter
three. The computed structure of a simplified cis-Pd complex of a bidentate
bisaminophosphine ligand gives valuable information on the coordination behavior.
Application of catalysts generated in situ from [Rh(cod)2]BF4 and bisaminophosphines
in the asymmetric hydrogenation of methyl (Z)-N-acetylaminocinnamate gave ee’s of
up to 91%. The contributions to stereoselection of individual aminophosphine moieties
are recognized.
Chapter four shows that the bisaminophosphine ligands form effective catalysts in the
Rh-catalyzed asymmetric hydroformylation of prochiral alkenes. The regioselectivities
for styrene and vinyl acetate were very good, while the enantioselectivities however
stay low with 12% and 51% respectively. HP-NMR studies indicated that equatorial -
equatorial coordination mode in the catalytic resting state is preferred for these ligands,
as was confirmed by HP-IR spectroscopy.
Finally in Chapter five mixed phosphonite-phospholane ligands are presented. They
are effective when applied in the Rh-catalyzed asymmetric hydroformylation of
styrene. Branched/linear ratio’s higher than 20 were obtained and the ee reached a
moderate 55%. NMR studies did not reveal the coordination mode of the ligands in the
trigonal bipyrimidal resting state of the catalytic cycle. The dependency of the catalyst
performance on the parameters temperature, pressure and L/Rh ratio were determined.
104
Samenvatting
Samenvatting
Onderzoek in Rhodium-Gekatalyseerde Asymmetrische Hydroformylering
In asymmetrische homogene metaalkatalyse is het van extreem belang om klassen van
chirale liganden beschikbaar te hebben die eenvoudig en modulair opgebouwd zijn en
wellicht zelfs geautomatiseerd gesynthetiseerd kunnen worden. Voor de academische
wereld is dit belangrijk om gedetailleerd structuur-prestatie relaties te bestuderen om
kennis te vergaren over de mechanismen van stereoselectie om uiteindelijk uit te komen
bij het rationele ontwerp van nieuwe katalysatoren voor een bepaald synthetisch
probleem. Vanuit het oogpunt van de chemische industrie zullen beschikbare
databanken aan liganden bijdragen aan snelle screening en optimalisatie van
katalysatoren voor een gegeven substraat, wat belangrijk is aangezien vooral in de fijn-
chemische industrie de beschikbare tijd voor ontwikkeling erg kort is.
Theoretisch inzicht, naast structuur-prestatie relaties, wordt verkregen door het
coördinatie-gedrag van liganden in de katalytisch actieve deeltjes te bestuderen door
structuur analyses en in situ spectroscopische technieken. Dit kan belangrijke data
opleveren voor verdere theoretische studies op een hoog niveau.
Hoofdstuk één geeft een introductie over asymmetrische hydroformylering, startend
met een historisch overzicht en eindigend met de toonaangevende ligandsystemen die
op dit moment de meest actieve en selectieve katalysatoren vormen. High-Throughput-
Experimentation, theoretische beschouwingen en spectroscopische onderzoeken
worden genoemd als belangrijke factoren die hierbij tot succes kunnen leiden.
In Hoofdstuk twee is de modulaire synthese van nieuwe symmetrisch en niet-