Non-Covalent Catalysis and Hydrogen Bonding


Research Paper (undergraduate), 2019
34 Pages, Grade: 1,0
Anonymous

Excerpt

Contents

1 Introduction

2 Knowledge
2.1 Hydrogen-Bond Catalysis
2.1.1 Dual Hydrogen-Bonding Donor Catalysis
2.1.2 Bifunctional Catalyst System
2.1.3 Single Hydrogen-Bond Donation
2.2 Cyclodiphosphazane as Catalyst

3 Aim

4 Results and Discussion
4.1 Synthesis of Precursors
4.1.1 Synthesis of Chiral Amin Ligand
4.1.2 Synthesis of Dichlorocyclodiphosph(III)azane
4.2 Synthesis and Characterization of Catalysts
4.3 Asymmetric Michael Addition

5 Conclusion and Outlook

6 Experimental part
6.1 General Experimental Conditions and Analytic Methods
6.2 Experimental Procedures
6.2.1 Synthesis of ligand
6.2.2 Synthesis of precursor
6.2.3 Synthesis of Asymmetric Catalyst with Oxygen
6.2.4 Synthesis of Asymmetric Catalyst with Sulfur
6.2.5 Asymmetric Michael addition in different solvents

7 References

8 Appendices

Abbreviation

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1 Introduction

Nowadays it is common to use catalysis in organic synthesis. It can help in orienting the substrates, lowering barriers to reaction and accelerating the rates of reaction. In addition to metal-ligand systems and biocatalysts, there is another class of catalysts – the organocatalysts which are free of any metals; like many enzymes. The organocatalysts often consist of chiral compounds. The output materials are easy to find in the nature. How these catalysts accelerate the reaction rates is steady a central question in organic synthesis. It is important to distinguish the interactions with the organic substrates between covalent and non-covalent bonds. The activation of a carbonyl compound by conversion into an enamine or into an iminium ion belongs to the covalent catalysis while to increase the electrophilicity of a carbonyl group by formation of hydrogen bondings is a typical example for non-covalent organocatalysis. Thus, the acceleration and the control of the reaction rates depend on formation of hydrogen bonds for non-covalent organocatalysis.1 It is possible to catalyse two hydrogen bonds which occurs in dual hydrogen bonding donors. This area and the asymmetric catalysis have received more attention in the last time.2

2 Knowledge

2.1 Hydrogen-Bond Catalysis

The idea of ​​catalyzing by hydrogen bonds was created by imitating nature. Hydrogen bonds are needed in enzymes to maintain their structure and functionality. These biological molecules catalyze chemical reactions and even those that form carbon-carbon bonds. The binding of ligands to receptors is one of the illustrations of the noncovalent interaction. The hydrogen-bond is defined as an interaction between a proton donor and an acceptor molecule. Chemists developed chiral catalysts that use hydrogen bonds to achieve high enantioselectivity. In many asymmetric synthesis, chiral organic small-molecule catalysts are used which implicated hydrogen-bonding to an electrophile to activate it.3 During the activation of the electrophile by the acidic catalyst, which forms hydrogen bonds to, for example, carbonyl compounds or imines, the LUMO energy levels of the C=O or C=N bonds are lowered, which may lead to a facilitated nucleophilic attack.4 However, the catalysts differ in their types and in their application. Therefore, it is possible to classify the catalysts in different mechanistic classes. 3

2.1.1 Dual Hydrogen-Bonding Donor Catalysis

In contrast to one hydrogen bonding, the interaction with two hydrogen bonds to a substrate is naturally stronger. Delivery of two bonds also proved to be a successful way to activate electrophiles in enzymes.1 With forming two hydrogen bonds to a reactant also the geometry will be defined.5 The electrophiles may consist of aldehydes, ketones, esters, imine derivatives, N-acyliminium ions and nitro compounds.1 Chiral urea and thiourea derivates act as asymmetric catalysts.2 Derived from them, new catalyst systems were developed, such as squaramides, P -triamides and cyclodiphosphazanes (figure 1).5

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Figure 1. Structures of thiourea, squaramide, P -triamide and cyclodiphosphazane.5

2.1.2 Bifunctional Catalyst System

An interesting study revealed the simultaneous activation of electrophile and nucleophile in a reaction called bifunctional catalysis. Squaramides, for example, often have an additional chiral scaffold which carries a basic unit. This base can be protonate and build a new hydrogen bond (figure 2).6 The bifunctional catalysts also include proline and cinchona alkaloid.1

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Figure 2. Transition state arising from the addition of 2-hydroxynaphthoquinone to β-nitro-styrene.

2.1.3 Single Hydrogen-Bond Donation

It is also possible to catalyze reactions with only one hydrogen bond, but this mechanism is much rarer than the double H-bond donation or bifunctional catalysis.1 A simple chiral alcohol can use the hydrogen bond to catalyze important cycloaddition reactions of a diene with various aldehydes. TADDOL, a chiral diol, also forms hydrogen bonds with carbonyls, therefore it is often used in enantioselective reductions of ketones as in hetero-Diels-Alder reactions as a catalyst (figure 3).7 In fact, there are structural similarities between TADDOL derivatives and phosphoric acids, which can also form a single hydrogen-bond for highly enantioselective catalysis.1

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Figure 3. Asymmetric hetero-Diels-Alder reaction of diene with aldehyde catalysed by 10mol% TADDOL derivate 1 (Ar=1-naphthyl).1

2.2 Cyclodiphosphazane as Catalyst

As briefly shown above, cyclodiphosphazanes are four-membered rings having alternating phosphorus (V) and nitrogen centers. This compound makes it possible to promote hydrogen-bonding catalysis.8 They are synthesized from dichloro-cyclodiphosph(III)azane and can then be equipped with ligand systems. The precursor is obtained by commercially available primary amines and PCl3 (figure 4).9

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Figure 4. General synthesis of dichlorocyclodiphosphazanes.9

As described, it is possible to form hydrogen-bonds by means of certain ligands. According to Klare et al. chiral primary amines were used as ligands. The product may specifically have different substituents or be symmetrically synthesized. In addition, the phosphorus atoms were oxidized by sulfur and cyclodiphosph(V)azanes were obtained (figure 5).5

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Figure 5. General synthesis of chiral cyclodiphosphazane catalysts.5 Protons which are responsible for hydrogen-bonds are marked in bold.

They succeeded in producing different catalysts (figure 6). The catalysts carry chiral DMDACH or aniline as ligands.

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Figure 6. Synthesized catalyst according Klare et al.5 Protons which could be responsible for hydrogen-bonds are marked in bold.

Their potential to form hydrogen-bond was investigated in an asymmetric Michael addition. All synthesized catalysts probably act as hydrogen-bond donors. However, the cis-configured symmetric catalyst proved to be the most efficient (figure 7). It was assumed that it catalyzes the reaction in a bifunctional mechanism.

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Figure 7. Asymmetric Michael addition reaction catalysed by cis - 2a according Klare et al.5

At the amines of the catalyst, hydrogen-bonds are generated to the nitro group of the olefin. This increases the nucleophilic attack of the olefin. The tertiary amine is available as a base and is protonated by 2-hydroxy-1,4-naphthoquinone. Thus, the 1,4-dioxo-1,4-dihydronaphthalene-2-olate is formed, which acts as a nucleophile and can attack the electrophilic site of β-nitrostyrene.

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Figure 8. Transition state arising from the addition of 2-hydroxynaphthoquinone to β-nitro-styrene. 5

Thus, in the transition state to both substrates hydrogen-bonds were formed over the catalyst (figure 8). Once through the diamide structure of the cyclodiphosphazane and on the other by the quaternary amine. 5

3 Aim

Since the application in the hydrogen-bonding catalysis of the chiral cyclodiphosph(V)azane as a catalyst was successful5, new catalysts with the same basic building block should be developed (figure 9). So only the ligands should be exchanged.

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Figure 9. Structure of the basic building block of the developed catalyst.

In Klare et al. the Michael addition of 2-hydroxynaphthoquinone to β-nitro-styrene was investigated with a catalyst which undermine the bifunctional mechanism. In this work the same addition should be examine, thus the new catalyst has to meet the same requirements. Therefore, it was necessary to select ligands such that amino groups are available for hydrogen-bonding to the nitro group and a tertiary amine can act as a base. Since only one framework acts as a base, it is possible to synthesize an asymmetric catalyst. Thus, 3,5-bis(trifluoromethyl)aniline and the chiral amin-cinchonidine were used as ligands (figure 10). In addition, the phosphorus should be oxidized by both sulfur and oxygen. To optimize the catalysis, only the solvents should be changed.

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Figure 10. Target molecules 8 and 9 of this work.

4 Results and Discussion

4.1 Synthesis of Precursors

4.1.1 Synthesis of Chiral Amin Ligand

The synthesis of 9-amino-(9-deoxy)epi-cinchonidine 11 was carried out via a modified protocol of Wan et al. starting from the hydroxylated form of cinchonidine 10 (figure 11).10 First, a Mitsunobu reaction with DPPA produced 9-azido(9-deoxy)epi-cinchonidine, which was then converted directly into the corresponding amine by a Staudinger reaction. The product was purified by column chromatography through dichloromethane, methanol and ammonia and 54% of the desired chiral amine was obtained, which was characterized by [1]H-NMR spectra (see appendices). The reaction was carried out under dry conditions.

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Figure 11. Synthesis pathway for the preparation of 9-amino-(9-deoxy)epi-cinchonidine 11.10

4.1.2 Synthesis of Dichlorocyclodiphosph(III)azane

The synthesis of dichlorocyclodiphosph(III)azane 12 was carried out according to a protocol of Bashall et al. from phosphorus trichloride and tributylamine under dry conditions (figure 12).11 The crude product was filtered off and freed from the solvent in an oil vacuum. The product was recovered via vacuum distillation. The residue was suspended in n -pentane and kept cool. Thus, 15% of the desired product was obtained and characterized by [31]P-NMR spectra (see appendices).

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Figure 12. Synthesis pathway for the preparation of dichlorocyclodiphosph(III)azane 12.11

4.2 Synthesis and Characterization of Catalysts

Braun also attempted to synthesize the asymmetric catalysts 8 and 9, but to no avail, so that the regulation was changed.12 He synthesized it analogous as in the synthesis of Klare et al. proceed.5 For this purpose, the dichlorocyclo-diphosph(III)azane 12 was first reacted under dry conditions with one equivalent of 3,5-bis(trifluoro)aniline and cinchonidine in succession. The deprotonation of the amines was carried out via triethylamine. The difference with Braun was that aniline and triethylamine were not mixed together for adding rather added one after the other. As well during addition of the aniline, Braun cooled down the batch to a temperature of -78°C and allowed the solution to stir for 24h at room temperature, while in this work the batch was cooled to 0°C upon addition of the aniline and was stirred for 24h at 35°C. After subsequent filtration, the resulting intermediate 13 was reacted with hydrogen peroxide or sulfur to oxidize the phosphorus (III) to phosphorus (V). The product was then purified by column chromatography with dichloromethane, methanol and concentrated ammonia. 24% of the oxygen oxidized 8 (from now o-cat) and 6% of the sulfur oxidized 9 (from now s-cat) product were obtained (figure 13). Both products could be successfully characterized ([1]H-NMR, [31]P-NMR, [19]F-NMR, HRMS - see appendices).

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Figure 13. Synthesis pathway for the both catalysts 8 (o-cat) and 9 (s-cat).11

[...]

Excerpt out of 34 pages

Details

Title
Non-Covalent Catalysis and Hydrogen Bonding
College
University of Cologne
Grade
1,0
Year
2019
Pages
34
Catalog Number
V492456
ISBN (eBook)
9783668995703
Language
English
Series
Aus der Reihe: e-fellows.net stipendiaten-wissen
Tags
non-covalent, catalysis, hydrogen, bonding
Quote paper
Anonymous, 2019, Non-Covalent Catalysis and Hydrogen Bonding, Munich, GRIN Verlag, https://www.grin.com/document/492456

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