Dendritic phenylacetylene cross-linking agent as well as preparation method and application thereof

Abstract

The invention relates to a dendronized phenylacetylene cross-linking agent as well as a preparation method and application thereof. The preparation method comprises the following steps: carrying out amidation reaction on dendronized active ester and amino alcohol to generate an intermediate product; and carrying out esterification reaction on the intermediate product, dialkynylbenzoic acid and a catalyst to generate the dendronized phenylacetylene cross-linking agent. The dendronized phenylacetylene monomer and the dendronized phenylacetylene cross-linking agent are used as main bodies, the good water solubility and temperature sensitivity of the cross-linking agent are utilized, temperature-sensitive aggregation of the monomer can be achieved under the condition that no additive exists, then in-situ cross-linking polymerization is conducted, and the uniformly-dispersed dendronized spiral polyphenylacetylene micro-nano gel is obtained. Good biocompatibility is shown, and potential application value can be achieved in the fields of biosensing, chiral drug delivery, biological tissue engineering and the like.

Description

Technical Field

[0001] The invention belongs to the field of chiral microgel materials, relates to a dendronized phenylacetylene crosslinking agent and a preparation method and application thereof, and in particular to a preparation method, performance and application of micro-nano gels based on amphiphilic dendronized helical polymers. Background Art

[0002] Chirality is widely present in nature and is a basic feature of life molecules (such as amino acids, sugars, nucleic acids, etc.). Inspired by these structural features, chiral polymers and functional materials have developed rapidly. Chiral microgels are a type of micro-nano gel material that has both chiral characteristics and cross-linked network structures. By simulating or enhancing natural chiral structures, they have expanded their wide applications in biomedicine and other fields. In the field of biosensing, chiral gels can achieve detection and quantitative analysis of biomolecules by specifically binding to target biomolecules; in the field of drug delivery, chiral nanogels can achieve drug delivery through chiral recognition mechanisms, improving targeting and biocompatibility. In the field of biological tissue engineering, chiral microgels can be used as support materials for cell culture. In a suitable microenvironment, chiral gels will affect cell growth and differentiation behavior. Chiral gels can also be used as immune adjuvants to mediate humoral immune responses and cellular immune responses, providing new ideas for immunotherapy of diseases such as tumors.

[0003] Existing methods for preparing chiral microgels mainly include template method, self-assembly method, physical or chemical cross-linking method, etc. Although these preparation methods provide a variety of options for the research and development of chiral micro-nanogels, they still face some challenges in practical applications. Traditional methods often require complex synthesis steps and strict reaction conditions, and it is difficult to achieve precise control and regulation of the chiral structure of microgels. In addition, the stability and functional performance of chiral microgels also need to be optimized.

[0004] Therefore, in order to promote the widespread application of chiral micro-nanogels in biomedicine, it is necessary to continuously optimize the preparation process and design a variety of chemical structures to give the materials multiple functions. The dendritic topological structure has an important influence on the properties of macromolecules and polymers. Dendritic polymers have a highly branched structure and can form cavities to achieve the encapsulation and controlled release of guest molecules. Functional groups can also be introduced into the center and end groups of dendritic polymers to give the polymers reactivity, stimulus responsiveness and biocompatibility. Studies have shown that some dendritic macromolecules can form confined hydrophobic microregions, construct microreactors, or simulate the microenvironment in vivo. How to utilize topological structures such as dendritic polymers and the dynamic chirality regulation of helical polyphenylene vinylene to prepare micro-nanogels in large quantities through green polymerization methods without the addition of chemical components such as emulsifiers and dispersants is a technical problem that needs to be solved urgently. This research has important practical value. Summary of the invention

[0005] The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a dendritic phenylacetylene crosslinking agent and a preparation method and application thereof. The dendritic phenylacetylene crosslinking agent of the present invention has good water solubility and temperature sensitivity, can realize the temperature-sensitive aggregation of dendritic phenylacetylene without additives, and then obtain uniformly dispersed dendritic helical polyphenylacetylene micro-nano gel by in-situ crosslinking polymerization, and optimize the conditions of the crosslinking polymerization reaction to quickly and efficiently prepare chiral micro-nano gel with uniform size distribution. In addition, the chiral characteristics of the gel respond to the temperature of the system and have dynamic controllability. The dynamic and static properties of the gel chirality can be adjusted by selecting the types of hydrophilic and hydrophobic dendritic monomers, showing good biocompatibility, and can have potential application value in the fields of biosensing, chiral drug delivery, biological tissue engineering, etc.

[0006] The purpose of the present invention can be achieved by the following scheme:

[0007] In a first aspect, the present invention provides a dendronized phenylacetylene crosslinking agent, the structural formula of the dendronized crosslinking agent is as follows:

[0008] Wherein, m=0-2, n=1-4, R is Me or Et, and the branched alkoxy ether unit includes any one of three arms, four arms and six arms.

[0009] In a second aspect, the present invention provides a method for preparing the dendronized phenylacetylene crosslinking agent, comprising: Amidation reaction with amino alcohols to generate intermediates In the presence of a catalyst, the intermediate product is esterified with diacetylene benzoic acid to generate a dendrite phenylacetylene crosslinking agent.

[0010]

[0011] As one embodiment of the present invention, the amidation reaction is carried out under ice bath conditions, and the esterification reaction is carried out under ice-salt bath conditions.

[0012] As an embodiment of the present invention, the amino alcohol includes any one of 2-aminoethanol, 3-amino-1-propanol, and 4-amino-1-butanol. The dialkynylbenzoic acid includes 2,5-dialkynylbenzoic acid.

[0013] As an embodiment of the present invention, the catalyst used in the esterification reaction includes at least one of 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0014] Furthermore, the dendronized phenylacetylene crosslinking agent of the present invention has good water solubility and temperature sensitivity, and its synthesis route is as follows:

[0015]

[0016] The specific steps include:

[0017] S1. In an ice bath, dendron active ester With amino alcohol ( m=0~2) and amidation reaction to generate intermediate product

[0018] S2. In an ice-salt bath, the intermediate product is mixed with 2,5-diynylbenzoic acid, 4-dimethylaminopyridine, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to undergo an esterification reaction to generate a dendritic phenylacetylene crosslinking agent.

[0019]

[0020] More specifically, the amidation reaction (a) in step S1 specifically comprises the following operations: n -Pf) was dissolved in dry DCM, different amino alcohols were added under ice bath conditions, and nitrogen was replaced after stirring evenly; an appropriate amount of triethylamine was added, and then naturally cooled to room temperature to react overnight. After the reaction was complete as detected by TLC plate, the reaction was stopped, washed with saturated brine, the organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the crude product was purified by chromatographic column to obtain the intermediate product R n -m-AP (colorless oily liquid);

[0021] Step S2: the esterification reaction (b) specifically comprises the following steps: n -m-AP and di-alkynylbenzoic acid were dissolved in dry DCM, and then 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice-salt bath conditions, and the mixed solution was replaced with nitrogen, and then naturally cooled to room temperature for reaction overnight. After the reaction was complete as detected by TLC plate, the reaction was stopped, washed with saturated brine, and the organic phase was dried with anhydrous magnesium sulfate. After evaporating the solvent, a crude product was obtained, which was then purified by chromatographic column to obtain the dendrite crosslinking agent R n -m-DEB (orange oily liquid).

[0022] In a third aspect, the present invention provides a method for preparing a dendrite helical polyphenylene vinylene micro-nano gel, comprising mixing a dendrite helical polyphenylene vinylene crosslinker with a dendrite monomer under anaerobic conditions, heating and aggregating the mixture (heating causes the mixed solution to form aggregates above the phase transition temperature), and then adding a catalyst to aggregate and react by in-situ polymerization to generate a dendrite helical polyphenylene vinylene micro-nano gel.

[0023] As an embodiment of the present invention, the structural formula of the dendron monomer is as follows:

[0024] Wherein, n=1-4, and R is Me or Et.

[0025] As an embodiment of the present invention, the concentration of the dendron monomer is 0.5 to 10 mg·mL -1 ; The molar ratio of the dendrite monomer to the dendrite phenylacetylene crosslinking agent is 5 to 20:1.

[0026] As an embodiment of the present invention, the temperature of the heating focus is 30-80°C, and the polymerization reaction time is 5-30 minutes. The present invention utilizes temperature to induce the dehydration collapse of the alkoxy ether unit to achieve microscopic and macroscopic aggregation of molecules.

[0027] As one embodiment of the present invention, the catalyst comprises [Rh(nbd)Cl]2.

[0028] As one embodiment of the present invention, the polymerization reaction is carried out under stirring at a stirring rate of 200 to 800 rpm.

[0029] As an embodiment of the present invention, the specific preparation steps of the polymerization reaction include: n -m-DEB) and dendron monomer (PA-R n ) was dissolved in (20 mL) distilled water according to a certain proportion, then added to a three-necked flask, and nitrogen was used for bubbling to remove oxygen. Under mechanical stirring, the mixed solution was heated in an oil bath to reach the preset reaction temperature. After the temperature stabilized, a catalyst was added using a microinjector to start the reaction. After a certain reaction time, stirring was stopped. After the solution was cooled, it was centrifuged and washed three times to remove the polymer that was not effectively cross-linked. It was then redispersed in deionized water at a certain concentration for other tests.

[0030] The hydrodynamic radius of the dendrite helical polyphenylene vinylene micro-nano gel of the present invention is 100-700 nm. The microgel of the present invention has good temperature sensitivity, and the volume shrinkage performance of the microgel can be controlled by temperature.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The present invention adopts a dendronized unit to modify a diacetylene crosslinking agent, so that the designed and synthesized dendronized phenylacetylene crosslinking agent has good water solubility and temperature sensitivity, and can prepare a large amount of micro-nano gels through aggregation in situ crosslinking polymerization with the dendronized monomer without any additives (emulsifiers, stabilizers, organic solvents, etc.), avoiding the use of toxic chemical additives; at the same time, the synthesis route is efficient, the experimental operation is simple, the reaction time is short (within about 10 minutes), and the yield is as high as more than 95%.

[0033] 2. The chiral characteristics of the micro-nano gel of the present invention respond to the system temperature and have dynamic controllability. The dynamic and static properties of the chirality of the gel can be adjusted by selecting the types of hydrophilic and hydrophobic dendron monomers, thereby affecting the recognition of the chirality of the micro-nano gel and the sustained release of chiral drugs, and even the internal microenvironment controlling the chiral catalytic reaction, etc., and has potential application value.

[0034] 3. The dendritic helical polyphenylene vinylene micro-nanogel of the present invention has a novel chemical structure and is thermosensitive. It can achieve volume contraction and dynamic chirality changes under temperature control and exhibits good biocompatibility, giving it application potential in the fields of biosensing, identification and sustained release of chiral drugs, cell microreactors, and biological tissue engineering. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0036] Figure 1 The intermediate product Me of Example 1 2 -1-AP H NMR spectrum;

[0037] Figure 2 is the cross-linking agent Me of Example 1 2 -1-DEB H NMR spectrum;

[0038] Figure 3 is the turbidity curve of the cross-linking agent aqueous solution in Example 1;

[0039] Figure 4 is the hydrodynamic radius of the dendrite helical polyphenylene vinylene microgel prepared in Examples 2 and 3;

[0040] Figure 5 This is an atomic force microscope morphology image of the dendrite helical polyphenylene vinylene micro-nanogel prepared in Example 2;

[0041] Figure 6 The variation trend of the hydrodynamic radius of the dendrite helical polyphenylene vinylene micro-nanogel prepared in Examples 2 and 3 with temperature;

[0042] Figure 7 The circular dichroism absorption curve of the medium-dendritic helical polyphenylene vinylene micro-nanogel prepared in Examples 2 and 3 changes with temperature;

[0043] Figure 8 The cytotoxicity of the dendritic helical polyphenylene vinylene micro-nanogel in Example 2;

[0044] Fig. 9 It is a cross-linking polymerization process;

[0045] Fig.10 This is a physical picture of the dendrite helical polyphenylene vinylene micro-nanogel in Example 2. DETAILED DESCRIPTION

[0046] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. The following examples are implemented on the premise of the technical solution of the present invention, provide detailed implementation methods and specific operation processes, and will help those skilled in the art to further understand the present invention. It should be pointed out that the protection scope of the present invention is not limited to the following embodiments, and several adjustments and improvements made under the premise of the concept of the present invention all belong to the protection scope of the present invention.

[0047] Reference for the synthesis of dendronized active esters (compounds 1a-1b in the literature): Li W., Zhang, X., et al. Doubly dendronized chiral polymers showing thermoresponsive properties [J]. J. Polym. Pol. Chem. 2013, 51(23), 5143-5152.

[0048] Synthesis reference of dendronized alkoxy ether chiral monomers (compounds PA-Ace and PA-ACm in the literature): Wang F., Zhou C., et al. Thermoresponsive Dendronized Poly(phenylacetylene)s Showing Tunable Helicity. Macromolecules 2019, 52(22), 8631-8642.

[0049] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0050] Example 1

[0051] In this embodiment, a type of dendrite phenylacetylene crosslinking agent is prepared by the following specific steps:

[0052] Step a. Synthesis of Me by amidation reaction 2 -1-AP process

[0053] Dendrimerize active ester Me 2-Pf (1g, 1.29mmol) was dissolved in dry DCM (15mL), 3-amino-1-propanol (123mg, 1.64mmol) was added under ice bath conditions, nitrogen was replaced after mixing, and then triethylamine (0.98mL, 6.45mmol) was added, and the reaction was allowed to proceed to room temperature overnight as the ice melted. After the reaction was complete as detected by TLC plate, the reaction was stopped. The organic phase was washed with saturated NaCl solution and a small amount of saturated NaSO4, and the organic phase was dried with MgSO4. After filtering and evaporating the solvent, the crude product was purified by chromatographic column to obtain the pure product Me 2 -1-AP;

[0054] Conduct structural characterization tests on intermediate products;

[0055] 1 H NMR (DMSO-d6, 25°C): δ = 1.62-1.69 (m, 2H, CH2), 3.23 (d, J = 2.9 Hz, 9H, CH3), 3.29 (q, J = 6.5 Hz, 2H, CH2), 3.39-3.62 (m, 26H, CH2), 3.67-3.77 (dt, J = 47.8, 4.8 Hz, 6H, CH2), 4.05-4.15 (dt, J = 39.8, 4.9 Hz, 6H, CH2), 4.48 (t, J = 5.2 Hz, 1H, OH), 7.16 (s, 2H, Ar-H), 8.36 (t, J = 5.6 Hz, 1H, NH). Figure 1 As shown;

[0056] Step b. Synthesis of crosslinking agent Me by esterification reaction 2 -1-DEB process

[0057] Compound Me 2 -1-AP (778 mg, 1.17 mmol) and 2,5-diynylbenzoic acid (203 mg, 1.02 mmol) were dissolved in dry DCM (15 mL), and then 4-dimethylaminopyridine (43 mg, 0.35 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (450 mg, 2.34 mmol) were added under ice-salt bath conditions, and the nitrogen was replaced and reacted at room temperature overnight. After the reaction was complete as detected by TLC plate, it was washed with saturated NaCl solution, the organic phase solution was dried over anhydrous MgSO4, and the solvent was evaporated. The crude product was purified by chromatographic column to obtain the pure product Me 2 -1-DEB is a dendronized phenylacetylene crosslinker, and its H NMR spectrum is as follows Figure 2 As shown;

[0058] Structural analysis test of the target product:

[0059] 1 H NMR (DMSO-d6, 25℃): δ=1.97-1.99 (p, J=6.6Hz, 2H, CH2), 3.22 (d, J=4.1Hz, 9H, CH3),3.40-3.61(m,26H,CH2),3.65-3.76(m,6H,CH2),4.04-4.14(m,6H,CH2), 4.32(t,J=6.3Hz,2H,CH2),4.47(s,1H,CH),4.59(s,1H,CH),7.16(s,2H,Ar-H ),7.60-7.70(m,2H,Ar-H),7.91(d,J=1.7Hz,1H,Ar-H),8.44-8.49(t,1H,NH).

[0060] The temperature sensitivity of the target product was characterized. The turbidity curve of the crosslinking agent aqueous solution was as follows: Figure 3 As shown, it can be seen that it has good water solubility and temperature sensitivity.

[0061] Example 2

[0062] refer to Fig. 9 The cross-linking polymerization process shown in the embodiment is composed of methoxyl dendron monomers. (PA-Me 2 ) and cross-linking agent (Me 2 -1-DEB) microgels were prepared by dissolving the dendritic monomer in distilled water to prepare 1 mg mL -1 20 mL of the monomer aqueous solution was taken and 4.1 mg of the crosslinking agent Me was added thereto. 2 -1-DEB (the molar ratio of monomer to cross-link is 5:1). Add the mixed solution into a three-necked flask and use nitrogen to bubble to remove oxygen. Under mechanical stirring (set the speed to 400rpm), heat the mixed solution to 70°C in an oil bath. After the temperature stabilizes, use a microinjector to add [Rh(nbd)Cl]2 to start the reaction. The molar ratio of [Rh(nbd)Cl]2 to the monomer is 1 / 250. After reacting for a certain period of time, stop stirring. After the solution cools down, perform three centrifugal washes to remove polymers that have not been effectively cross-linked. Then reconfigure to 1 mg·mL -1 The gel solution (reaction yield 96%), the actual gel is as follows Fig.10 shown.

[0063] Example 3

[0064] In this embodiment, the ethoxylated dendron monomer (PA-Et 2 ) and cross-linking agent (Et2 -1-DEB, the synthesis method thereof is referred to Example 1) to prepare microgel. The specific steps are as follows: the dendron monomer is dissolved in distilled water to prepare 1 mg·mL -1 20 mL of the monomer aqueous solution was taken and 4.3 mg of the crosslinking agent Et 2 -1-DEB (the molar ratio of monomer to cross-link is 5:1). Add the mixed solution into a three-necked flask and use nitrogen to bubble to remove oxygen. Under mechanical stirring (set the speed to 400rpm), heat the mixed solution to 40°C in an oil bath. After the temperature stabilizes, use a microinjector to add [Rh(nbd)Cl]2 to start the catalytic reaction. The molar ratio of [Rh(nbd)Cl]2 to the monomer is 1 / 250. After a certain reaction time, stop stirring. After the solution is cooled, perform three centrifugal washes to remove polymers that have not been effectively cross-linked. Then reconfigure to 1mg·mL -1 of gel solution (reaction yield 95%).

[0065] Example 4

[0066] In this example, the size and distribution of the gels prepared in Examples 2 and 3 were analyzed, and characterization tests were performed on the hydrated state and the dry state thereof. The specific steps are as follows:

[0067] Step a. Dilute the microgel solution to 0.1 mg mL -1 , and then tested by dynamic light scattering instrument. h are 152 nm and 572 nm, respectively, and the polydispersity indices are 0.03 and 0.29, respectively.

[0068] Among them, the hydrodynamic radius of the dendrite helical polyphenylene vinylene microgel is as follows: Figure 4 shown.

[0069] Step b. Observe the morphology of the microgel prepared in Example 2 using an atomic force microscope (AFM). -1 ) was coated on a mica substrate by a spin coater, and AFM testing was performed after the solvent evaporated and it was completely dried.

[0070] Among them, the morphology of dendrite helical polyphenylene vinylene microgels is characterized as follows: Figure 5 As shown in A. Figure 5 As shown in B, the nanogel prepared in Example 2 has a gel diameter of 201±21 nm and a height of 27±3 nm in a dry state.

[0071] Example 5

[0072] In this embodiment, the temperature sensitivity and chirality of the microgel are tested, and the specific steps are as follows:

[0073] Step a. Dilute the gel aqueous solution prepared in Examples 2 and 3 to 0.05 mg·mL -1 , and then track the change of the hydrodynamic radius of the gel with temperature through dynamic light scattering characterization;

[0074] Among them, the R h With the change of temperature Figure 6 shown.

[0075] Step b. Dilute the gel aqueous solution prepared in Examples 2 and 3 to 0.1 mg·mL -1 Then, the chirality of the dendritic helical polyphenylene vinylene microgels was characterized by circular dichroism spectroscopy as a function of temperature.

[0076] The chirality of the dendritic helical polyphenylene vinylene microgel changes with temperature. Figure 7 As shown. Gels made from different monomers have different chiral stabilities: methoxy system gels have chiral stability, and ethoxy system gels have chiral dynamics. The gel of the present invention has characteristic temperature-sensitive behavior, and the size can be controlled by the hydrophilicity and hydrophobicity of the monomers, which further determines the stability and dynamics of the chirality of the temperature-induced micro-nano gel.

[0077] Example 6

[0078] In this example, the nanogel obtained in Example 2 was dissolved in a cell culture medium and a cell suspension was prepared with human cancer cells. The cell suspension was aspirated after different days, the cells were stained, and then observed and recorded under a confocal laser scanning microscope (CLSM). The cell activity photos were then analyzed to evaluate the cell survival rate. After 7 days of observation of the cells, the cells had a high survival rate, indicating that the dendritic polyphenylene vinylene micro-nano gel spheres have good biocompatibility and are expected to be applied to biomedicine and other fields. Among them, the cytotoxicity of the dendritic helical polyphenylene vinylene microgel is as follows: Figure 8 shown.

[0079] The embodiments of the present invention are described above in conjunction with the accompanying drawings, but the present invention is not limited to the above embodiments. Various changes can be made according to the purpose of the invention of the present invention. Any changes, modifications, substitutions, combinations, and simplifications made according to the spirit and principle of the technical solution of the present invention should be equivalent replacement methods. As long as they meet the purpose of the present invention and do not deviate from the technical principles and inventive concepts of the method for preparing chiral microgels based on the aggregation of dendronized chiral phenylacetylene monomers through in-situ cross-linking reaction, they all belong to the protection scope of the present invention.

Claims

1. A dendrite phenylacetylene crosslinking agent, characterized in that: The structural formula of the dendrite crosslinking agent is as follows: Wherein, m=0-2, n=1-4, and R is Me or Et.

2. A method for preparing the dendronized phenylacetylene crosslinking agent as claimed in claim 1, characterized in that: The preparation method comprises: Amidation reaction with amino alcohols to generate intermediates In the presence of a catalyst, the intermediate product is esterified with diacetylene benzoic acid to generate a dendrite phenylacetylene crosslinking agent.

3. The preparation method according to claim 2, characterized in that: The amino alcohol includes any one of 2-aminoethanol, 3-amino-1-propanol and 4-amino-1-butanol.

4. The preparation method according to claim 2, characterized in that: The dialkynylbenzoic acid includes 2,5-dialkynylbenzoic acid.

5. The preparation method according to claim 2, characterized in that: The catalyst includes at least one of 4-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

6. A method for preparing a dendritic helical polyphenylene vinylene micro-nano gel, characterized in that: The preparation method comprises: under anaerobic conditions, mixing the dendronized phenylacetylene crosslinking agent as claimed in claim 1 with a dendronized monomer, heating and aggregating, and then adding a catalyst to aggregate and react in situ to generate a dendronized helical polyphenylacetylene micro-nano gel.

7. The preparation method according to claim 6, characterized in that: The structural formula of the dendron monomer is as follows: Wherein, n=1-4, and R is Me or Et.

8. The preparation method according to claim 6, characterized in that: The concentration of the dendron monomer is 0.5 to 10 mg mL -1 ; The molar ratio of the dendrite monomer to the dendrite phenylacetylene crosslinking agent is 5 to 20:

1.

9. The preparation method according to claim 6, characterized in that: The temperature of the heating and focusing is 30 to 80° C.; the time of the polymerization reaction is 5 to 30 minutes.

10. The preparation method according to claim 6, characterized in that: The catalyst includes [Rh(nbd)Cl]2.

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