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Synlett 2013; 24(18): 2419-2422
DOI: 10.1055/s-0033-1339851
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© Georg Thieme Verlag Stuttgart · New York

Structural Characterisation of Cu Complexes of Chiral Ferrocenyl Diphos­phine Ligands

Francesca Caprioli
a   Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands   Fax: +31(50)3634296   Email: s.harutyunyan@rug.nl   Email: a.j.minnaard@rug.nl
,
Martin Lutz
b   Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
,
Auke Meetsma
a   Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands   Fax: +31(50)3634296   Email: s.harutyunyan@rug.nl   Email: a.j.minnaard@rug.nl
,
Adriaan J. Minnaard
a   Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands   Fax: +31(50)3634296   Email: s.harutyunyan@rug.nl   Email: a.j.minnaard@rug.nl
,
Syuzanna R. Harutyunyan*
a   Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands   Fax: +31(50)3634296   Email: s.harutyunyan@rug.nl   Email: a.j.minnaard@rug.nl
› Author Affiliations
Further Information

Publication History

Received: 19 August 2013

Accepted: 22 August 2013

Publication Date:
27 September 2013 (online)

 
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Abstract

Copper complex formation of JosiPhos-type ligands leads to extreme differences in solubility between the racemate and the enantiomers.


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Key words

copper complex - chiral ferrocenyl ligand - amplification - solubility

Over the last few decades, many asymmetric catalytic transformations have been developed using chiral ligands in combination with transition metals.[1] The introduction of the bidentate chiral phosphine DIOP by Kagan marked the beginning of the era of bidentate phosphine ligands in asymmetric catalysis. Examples comprising P,P ligands are BINAP, DuPhos, DiPAMP, TRAP, JosiPhos, XyliPhos, TaniaPhos and WalPhos-type ligands.[2] These ligands have been used in many asymmetric transformations such as hydrogenation, alkene hydroboration, hydrophosphination, Heck reactions, conjugate additions and so on.[1b]

Recently, we reported a dramatic asymmetric amplification in the 1,2-addition of Grignard reagents to enones in t-BuOMe (Scheme [1]), catalysed by a copper complex of the chiral ferrocenyl diphosphine ligand rev-JosiPhos.[3] It was made plausible that the strong asymmetric amplification is not specific to this particular reaction but is in fact due to significant differences in the solubility of the racemic and the enantiopure catalyst. Complexation of a transition metal with a number of chiral diphosphine ligands led to extreme differences in solubility between the enantiopure and the racemic complexes.[3c]

Here we report the structural characterisation of a number of copper complexes of racemic and enantiopure ferrocenyl diphosphine ligands in the solid state and in solution. We discuss their physicochemical properties and provide an explanation for the previously obtained amplification phenomenon.

The dramatic difference in solubility of the chiral copper complex of rev-JosiPhos found in our previous studies[3c] is the primary factor for the previously observed asymmetric amplification.

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Syuzanna R. Harutyunyanis currently a tenured Associate Professor in Synthetic Organic Chemistry at the University of Groningen. Harutyunyan’s group research activities include enantioselective synthesis, organometallic reactions, catalysis, autocatalysis, mechanistic studies. Part of this work has resulted in winning the prestigious Solvias Ligand Contest in 2011 and highly competitive NWO-Vidi award in 2012. Before joining the University of Groningen to occupy a tenure-track position, she carried out research in Armenia, Russia, Poland, Belgium, and in the Netherlands. She worked for two years as a senior scientist at Tibotec-JanssenPharmaceutica-J&J (Belgium). The research was focused on the development of new patent-free metathesis catalysts, for synthesis of an anti-hepatitis drug and the implementation of new procedures to scale up production. During her post-doctoral with Prof. Ben Feringa (Netherlands) her research led to the discovery of the first enantioselective catalytic methodologies using Grignard reagents, and revealed the mechanisms of these reactions and application of these methodologies in total synthesis of natural products. As a visiting scientist in the group of Prof. K. Grela (Poland) she worked on the synthesis and the application of metathesis catalysts. During her PhD research under supervision of Prof. Yu. N. ­Belokon (Russia) she developed new strategies for enantioselective synthesis of amino acids in phase-transfer-conditions. Syuzanna obtained her masters degree in pharmacology at Yerevan State University.

Therefore we chose copper complexes of rev-JosiPhos and the related ligands JosiPhos and TaniaPhos, all commonly used in asymmetric catalysis, for the studies reported here (Scheme [2]).[4] Both the racemic and the enantiopure copper complexes were prepared in t-BuOMe or CH2Cl2 (0.015 M) by mixing the corresponding chiral racemic and enantiopure ligands with the corresponding amount of copper salt at room temperature for one hour. In both solvents a significant amount of precipitate formed in the case of the racemic complex of rev-JosiPhos, while the enantiopure complex was fully soluble. A racemic sample was obtained by simple filtration of the reaction mixture and the enantiopure complex was obtained by removal of the remaining solvent. In the case of JosiPhos and TaniaPhos both the racemic and the enantiopure complexes were obtained by solvent removal either from t-BuOMe or CH2Cl2. To understand the structural differences between the racemic and the enantiopure complexes, we first studied the species formed in solution. The initial hypothesis was that dinuclear and mononuclear species can have different solubilities, and depending on whether the ligand is racemic or enantiopure, either of the two species is formed. To confirm this hypothesis we first studied solutions (in CH2Cl2 and t-BuOMe) and solid samples of both racemic and enantiopure complexes using high resolution ESI–MS and DART–MS[5] spectrometry. Unfortunately, molecular ions corresponding to dimeric and monomeric species were found for all samples, so this was inconclusive.

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Scheme 1 Asymmetric amplification in 1,2-addition of Grignard reagents to ketones
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Scheme 2 Structures of chiral ferrocenyl diphosphine ligands used for the synthesis of racemic and enantiopure copper complexes

No significant differences were observed in the 1H NMR, 31P NMR, and 13C NMR spectra for the copper complexes of the racemic and enantiopure ligands.

To reveal the composition of the copper complexes in the solid phase, crystals of racemic and enantiopure copper complexes of all three ligands were grown and subjected to X-ray crystallography.[6,7]

The crystal structures of the Cu complexes of rev-JosiPhos show a dimeric structure for both the racemate[8] [9] and the single enantiomer, albeit with a different symmetry (Figure [1, a] and b).[6,7]

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Figure 1 X-ray crystal structures[6] [7] of the copper bromide complexes of rev-JosiPhos: (a) rac-CuBr-rev-JosiPhos; (b) enant-CuBr-rev-JosiPhos (the asymmetric unit consists of a dinuclear copper complex, with a molecule of water present in the cell).[6a]

In both cases the unit cell consists of one moiety of a dinuclear copper complex, bridged by two Br atoms. Analysis of the crystal structures of the racemate and single enantiomer of Cu/JosiPhos revealed monomeric structures (Figure [2a]). Similarly the racemate and the single enantiomer[7] of Cu/TaniaPhos showed monomeric structures.

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Figure 2 X-ray crystal structures[6] [7] of the copper bromide complexes of JosiPhos and TaniaPhos: (a) rac-CuBr-JosiPhos; (b) rac-CuBr-TaniaPhos. For enantiopure structures of CuBr-JosiPhos and CuBr-TaniaPhos see ref. 4 and Supporting Information correspondingly.

When we compared the crystal structures of the racemates and the single enantiomers, we made the interesting observation that racemic Cu/rev-JosiPhos and Cu/JosiPhos have a higher density and a higher packing index than the single enantiomers (Table [1]).[10]

Table 1 Crystal Packing Characteristics[6] [7]

CuBr-Ligand

CCDC number

Space group

Dx [g/cm]

K.P.I.[10]

rac-CuBr-rev-JosiPhos

CCDC 908802

C2/c (no. 15)

1.545

69.8%

enant-CuBr-rev-JosiPhos

CCDC 610500a

C2221 (no. 20)

1.475

67.0%

rac-CuBr-JosiPhos

CCDC 908803

P1 (no. 2)

1.540

69.7%

enant-CuBr-JosiPhos

CCDC 261573

P21 (no. 4)

1.529

69.3%

rac-CuBr-TaniaPhos

CCDC 908804b

P21/c (no. 14)

1.539

68.0%

enant-CuBr-TaniaPhos

CCDC 909403

P212121 (no. 19)

1.539

68.5%

a Monohydrate.

b CH2Cl2 solvate.

According to the principle of ‘close packing’[10] this is a sign for higher stability of the crystal. Enantiopure CuBr-rev-JosiPhos is characterised by strong intermolecular O–H···Br hydrogen bonds forming a one-dimensional chain in the crystal structure. Racemic CuBr-rev-JosiPhos has no such strong intermolecular interactions, nevertheless its density is higher than that of the single enantiomer. The exception is Cu/TaniaPhos, for which the densities of the racemic and enantiopure crystals were similar. This could be due to the co-crystallized solvent (CH2Cl2) in the racemic crystals.

Combined MS spectrometry, NMR spectroscopy and X-ray spectroscopy confirmed that both mononuclear and dinuclear species can be present in solution and the solid state for both the racemic and the enantiopure complexes of all ligands studied. It is a general trend that the stability of racemates is higher than that of single enantiomers;[11] however, the resulting difference in solubility is usually not sufficient to provide enantiopure supernatants through preferential crystallization of the racemate from the scalemic solution.[11]

One the other hand, the introduction of intermolecular ­interactions, e.g. H-bonding or ionic interactions, can ­amplify the solubility difference.[12]

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Scheme 3 (a) Possible copper species; (b) four scenarios to rationalise the observed precipitation phenomenon

In the present systems there is no possibility for these kinds of intermolecular interactions when free ligands are considered. Hence the formation of metal complexes acts as a surrogate for such interactions leading to the formation of mononuclear and/or dinuclear homochiral and heterochiral species (Scheme [3, a]). It is reasonable to assume that this leads to the large difference in solubility of the dinuclear homo- and heterochiral species which results in an enantiopure supernatant. However, it is not necessarily the case that the precipitate is the dinuclear complex as in some cases the mononuclear complexes have been obtained as racemic and enantiopure solids. Hence, the observed solid-solution behaviour can be accounted for with large differences in solubility between (Scheme [3, b]): (1) mononuclear enantiopure and racemic complexes; (2) mononuclear enantiopure and dinuclear heterochiral complexes; (3) dinuclear homochiral and heterochiral complexes; (4) dinuclear homochiral and racemic complexes. None of these cases can be excluded. What is certain is that metal complexation causes higher geometric rigidity of the complex, compared to the free ligands, which in turn enhances the differences in packing of racemic and enantiopure complexes.


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Acknowledgment

We thank Dr B. Pugin (Solvias) for a generous gift of a ligand kit for initial screening. Financial support from the Netherlands Organization for Scientific Research (NWO-Vidi, S.R.H.) is acknowledged.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Syuzanna R. Harutyunyanis currently a tenured Associate Professor in Synthetic Organic Chemistry at the University of Groningen. Harutyunyan’s group research activities include enantioselective synthesis, organometallic reactions, catalysis, autocatalysis, mechanistic studies. Part of this work has resulted in winning the prestigious Solvias Ligand Contest in 2011 and highly competitive NWO-Vidi award in 2012. Before joining the University of Groningen to occupy a tenure-track position, she carried out research in Armenia, Russia, Poland, Belgium, and in the Netherlands. She worked for two years as a senior scientist at Tibotec-JanssenPharmaceutica-J&J (Belgium). The research was focused on the development of new patent-free metathesis catalysts, for synthesis of an anti-hepatitis drug and the implementation of new procedures to scale up production. During her post-doctoral with Prof. Ben Feringa (Netherlands) her research led to the discovery of the first enantioselective catalytic methodologies using Grignard reagents, and revealed the mechanisms of these reactions and application of these methodologies in total synthesis of natural products. As a visiting scientist in the group of Prof. K. Grela (Poland) she worked on the synthesis and the application of metathesis catalysts. During her PhD research under supervision of Prof. Yu. N. ­Belokon (Russia) she developed new strategies for enantioselective synthesis of amino acids in phase-transfer-conditions. Syuzanna obtained her masters degree in pharmacology at Yerevan State University.
Zoom Image
Scheme 1 Asymmetric amplification in 1,2-addition of Grignard reagents to ketones
Zoom Image
Scheme 2 Structures of chiral ferrocenyl diphosphine ligands used for the synthesis of racemic and enantiopure copper complexes
Zoom Image
Figure 1 X-ray crystal structures[6] [7] of the copper bromide complexes of rev-JosiPhos: (a) rac-CuBr-rev-JosiPhos; (b) enant-CuBr-rev-JosiPhos (the asymmetric unit consists of a dinuclear copper complex, with a molecule of water present in the cell).[6a]
Zoom Image
Figure 2 X-ray crystal structures[6] [7] of the copper bromide complexes of JosiPhos and TaniaPhos: (a) rac-CuBr-JosiPhos; (b) rac-CuBr-TaniaPhos. For enantiopure structures of CuBr-JosiPhos and CuBr-TaniaPhos see ref. 4 and Supporting Information correspondingly.
Zoom Image
Scheme 3 (a) Possible copper species; (b) four scenarios to rationalise the observed precipitation phenomenon