Discovery and Synthesis Optimization of Isoreticular Al(III) Phosphonate-Based Metal-Organic Framework Compounds Using High-Throughput Methods

Summary

The targeted synthesis of new metal-organic frameworks (MOFs) is difficult, and their discovery depends on the knowledge and creativity of the chemist. High-throughput methods allow complex synthetic parameter fields to be explored quickly and efficiently, accelerating the process of finding crystalline compounds and identifying synthetic and structural trends.

Abstract

High-throughput (HT) methods are an important tool for the fast and efficient screening of synthesis parameters and the discovery of new materials. This manuscript describes the synthesis of metal-organic frameworks (MOFs) from solution using an HT reactor system, resulting in the discovery of various phosphonate-based MOFs of the composition [Al₂H_12-x(PMP)₃]Cl_x∙6H₂O (H₄PMP = N,N '-piperazine bis(methylenephosphonic acid)) for x = 4, 6, denoted as Al-CAU-60-xHCl, containing trivalent aluminum ions. This was accomplished under solvothermal reaction conditions by systematically screening the impact of the molar ratio of the linker to the metal and the pH of the reaction mixture on the product formation. The protocol for the HT investigation includes six steps: a) synthesis planning (DOE = design of experiment) within the HT methodology, b) dosing and working with in-house developed HT reactors, c) solvothermal synthesis, d) synthesis workup using in-house developed filtration blocks, e) characterization by HT powder X-ray diffraction, and f) evaluation of the data. The HT methodology was first used to study the influence of acidity on the product formation, leading to the discovery of Al-CAU-60∙xHCl (x = 4 or 6).

Introduction

Metal-organic frameworks (MOFs) are porous, crystalline compounds whose structures consist of metal-containing nodes, like metal ions or metal-oxygen clusters, which are connected by organic molecules (linkers)¹. By varying the metal-containing nodes as well as the linker, a variety of compounds can be obtained that exhibit a wide range of properties and therefore have potential applications in different fields¹.

The stability of a material is important for its application^1,2,3. Therefore, MOFs containing tri- or tetravalent metal ions, such as Al³⁺, Cr³⁺, Ti⁴⁺, or Zr⁴⁺, with carboxylate² or phosphonate⁴ linker molecules have been the focus of many investigations^5,6,7. In addition to the direct synthesis of stable MOFs, the enhancement of stability through post-synthetic modifications as well as the formation of composites is a field of interest². Phosphonate-based MOFs have been less often reported compared to carboxylate-based MOFs⁸. One reason is the higher coordination flexibility of the CPO₃^2- group compared to the -CO₂^- group, which often leads to the formation of dense structures and greater structural diversity^8,9,10,11. In addition, phosphonic acids often must be synthesized, as they are rarely available on the market. While some metal phosphonates exhibit exceptional chemical stability¹⁰, systematic access to isoreticular metal phosphonate MOFs, which allows the tuning of properties, is still a topic of high relevance^12,13. Different strategies for the synthesis of porous metal phosphonates have been investigated, such as incorporating defects into otherwise dense layers, for example, by partially replacing phosphonate with phosphate ligands^4,14. However, as defective structures are poorly reproducible, and the pores are not uniform, other strategies have been developed. In recent years, the use of sterically demanding or orthogonalized phosphonic acids as linker molecules have emerged as a suitable strategy for the preparation of porous metal phosphonates^{4,8,10,11,13,15,16,17,18}. However, a universal synthesis route for porous metal phosphonates has not yet been discovered. As a result, the synthesis of metal phosphonates is often a process of trial and error, requiring the investigation of many synthesis parameters.

The parameter space of a reaction system includes chemical and process parameters and can be vast¹⁹. It consists of parameters such as the type of starting material (metal salt), molar ratios of starting materials, additives for pH adjustment, modulators, type of solvent, solvent mixtures, volumes, reaction temperatures, times, etc.^19,20. A moderate number of parameter variations can easily result in several hundred individual reactions, making a carefully considered synthesis plan and well-chosen parameter space necessary. For example, a simple study using six molar ratios of the linker to the metal (e.g., M:L = 1:1, 1:2, ... to 1:6) and four different concentrations of an additive and keeping the other parameter constant, leads already to 6 x 4 = 24 experiments. Using four concentrations, five solvents, and three reaction temperatures would necessitate carrying out the 24 experiments 60 times, resulting in 1,440 individual reactions.

High-throughput (HT) methods are based on the concepts of miniaturization, parallelization, and automation, to varying degrees depending on the scientific question being addressed^19,20. As such, they can be used to accelerate the investigation of multi-parameter systems and are an ideal tool for the discovery of new compounds, as well as synthesis optimization^19,20. HT methods have been used successfully in different fields, ranging from drug discovery to materials science²⁰. They have also been used for the investigation of porous materials such as zeolites and MOFs in solvothermal reactions, as recently summarized²⁰. A typical HT workflow for solvothermal synthesis consists of six steps (Figure 1)^19,20,21: a) selection of the parameter space of interest (i.e., the design of experiment [DOE]), which can be done manually or by using software; b) dosing of the reagents into the vessels; c) solvothermal synthesis; d) isolation and workup; e) characterization, which is typically done with powder X-ray diffraction (PXRD); and f) data evaluation, which is followed by step one again.

Parallelization and miniaturization are achieved in solvothermal reactions through the use of multiclaves, often based on the well-established 96-well plate format most commonly used in biochemistry and pharmacy^19,20,22,23. Various reactor designs have been reported and several groups have constructed their own reactors^19,20. Reactor choice depends on the chemical system of interest, especially the reaction temperature, (autogenous) pressure, and reactor stability^19,20. For example, in a systematic study of zeolitic imidazolate frameworks (ZIFs), Banerjee et al.²⁵ used the 96-well glass plate format to perform over 9600 reactions²⁴. For reactions under solvothermal conditions, customized polytetrafluoroethylene (PTFE) blocks, or multiclaves with 24 or 48 individual PTFE inserts, have been described among others by the Stock group^19,20. They are routinely employed, for example, in the synthesis of metal carboxylates and phosphonates. As such, Reinsch et al.²⁵ reported the advantages of the methodology in the field of porous aluminum MOFs²⁵. The in-house made HT reactor systems (Figure 2), which allow 24 or 48 reactions to be studied simultaneously, contain PTFE inserts with a total volume of 2.655 mL and 0.404 mL, respectively (Figure 2A,B). Usually, no more than 1 mL or 0.1 mL, respectively, is used. While these reactors are used in conventional ovens, microwave-assisted heating using SiC blocks and small glass vessels has also been reported²⁶.

The automation of studies leads to time savings and improved reproducibility, as influence of the human factor is minimized²⁰. The degree to which automation has been used varies strongly^19,20. Fully automated commercial systems, including pipetting²⁰ or weighting capabilities²⁰, are known. A recent example is the use of a liquid-handling robot to study ZrMOFs, reported by the group of Rosseinsky²⁷. Automated analysis can be performed by PXRD using a diffractometer equipped with an xy stage. In another example, a plate reader was used to screen solid-state catalysts, mainly MOFs, for HT screening of nerve agent degradation²⁸. Samples can be characterized in a single run without the need for manual sample or position changes. Automation does not eliminate human error, but it reduces the possibility of its occurring^19,20.

Ideally, all steps in a HT workflow should be adapted in terms of parallelization, miniaturization, and automation to eliminate possible bottlenecks and maximize efficiency. However, if it is not possible to establish a HT workflow in its entirety, it may be helpful to adopt selected steps/tools for one's own research. The use of multiclaves for 24 reactions is particularly useful here. The technical drawings of the in-house made equipment used in this study (as well as others) are published for the first time and can be found in Supplementary File 1, Supplementary File 2, Supplementary File 3, and Supplementary File 4.

Protocol

In this protocol, the HT investigation of chemical systems to discover new crystalline materials, using Al-CAU-60²⁹ as an example, is described.

1. Design of Experiment (DOE)

NOTE: The first step is to set up a synthesis plan, which requires knowledge of the reactor setup (Figure 2), reactants, and solvents used. This synthesis planning procedure is adapted to performing 24 or 48 reactions under a specific temperature-time program, for which in-house made steel multiclaves are used to perform 24 (Figure 2A) or 48 reactions (Figure 2B) at once. The reactors are in-house made PTFE inserts with a used reagent/solvent volume of 1 mL (PTFE reactor for carrying out 24 reactions in the steel multiclave) or 100 µL (PTFE reactor for carrying out 48 reactions in the steel multiclave). The technical drawings of the reactor setup can be found in Supplementary File 1 and Supplementary File 2 respectively.

1. First, determine the parameter space to be investigated. Therefore, make decisions about an initial number of reactions, metal source, and linker molecule, as well as the use of additives and solvent.
   1. For the chosen example of Al-CAU-60, carry out 24 reactions using AlCl₃∙6H₂O as a metal source and N, N′-piperazine-bis(methylenephosphonic acid) (H₄PMP) as a linker molecule. Furthermore, use aqueous solutions of NaOH and HCl as additives to study the influence of the pH of the reaction mixture on product formation.1
      NOTE: The choice of parameters is usually based on published synthesis procedures or principles based on fundamental chemical knowledge. However, for the successful discovery of new materials, a broader variation of the reaction parameters should be applied (i.e., a certain degree of diversity of the reaction parameters should be considered). The number of parameters to be varied and the type of variations can be based on different principles. In the simplest form, only one parameter should be changed at a time. For example, a fixed metal salt concentration in combination with varying linker molecule concentrations can be used to investigate different linker-to-metal ratios. However, the investigation can also use different molar ratios of the linker to the metal and other solvents or additives. The accessible parameter space is limited by the solubility of the starting materials (amount and solvent type) in cases where only solutions are used²¹. The dosing of solids extends the accessible parameter space²⁰.
2. Specify the parameter space. For this purpose, choose and calculate quantities of starting materials (molar ratios) and solvent volumes.
   1. For the chosen example of Al-CAU-60, vary the molar ratio of H₄PMP to Al³⁺ between 4:1 and 0.3:1 in six steps: 4:1, 3:1, 2:1, 1:1, 0.5:1, 0.3:1. Carry out all six syntheses with different additive ratios; study one molar ratio of NaOH to Al³⁺ (1:1) and two molar ratios of HCl to Al³⁺ (20:1 and 40:1), as well as one without any additive. Use a spreadsheetto calculate the quantities of starting materials required for this, which can be found in the additional information.

2. Dosing and solvothermal synthesis

1. Prepare the stock solutions in a fume hood by following the standard protocol for preparing stock solutions of the reagents.
   CAUTION: H₄PMP, AlCl₃∙6 H₂O, HCl, and NaOH are corrosive substances, which cause severe skin burns and eye damage on contact. Wear personal protective equipment when working with these substances.
   1. For the chosen example of Al-CAU-60, prepare the following reagents according to the spreadsheet in the supporting information (Supplementary Table 1): hydrochloric acid solution with a concentration of 10 mol/L, sodium hydroxide solution with a concentration of 1 mol/L, and an AlCl₃∙6H₂O solution with a concentration of 1 mol/L.
      NOTE: Product formation can also depend on the aggregation state of the added reagents. For solids, the particle size can have an effect due to the dissolution rate. A decision should be made at the beginning of the study whether to use solids or solutions to allow for systematic evaluation.
2. Insert the discs into the sample plate (Figure 3A).
3. Transfer reagents, additives, and solvents into the PTFE inserts (Figure 3B).
   1. For the chosen example of Al-CAU-60, first add the linker H₄PMP as a solid to the PTFE inserts, then add the aluminum chloride solution, the demineralized water, and the solution of additives (NaOH or HCl) with a pipette in accordance with the values calculated in the spreadsheet in the supporting information (Supplementary Table 1).
      NOTE: The order in which the PTFE inserts are filled can also influence product formation; therefore, the order of starting materials should be chosen in advance and kept the same throughout the study to allow a systematic evaluation.
4. Insert the filled PTFE inserts into the sample plate.
5. Mark the ground plate of the reactor in a way that allows the identification of the PTFE inserts later. Insert the sample plate with the filled PTFE inserts into the ground plate of the reactor (Figure 3C).
6. Prepare two PTFE sheets (with a thickness of 0.1 mm) to cover the sample plates.
7. Place the PTFE sheets on the sample plate (Figure 3D).
8. Ensure that the PTFE sheet is correctly positioned and fits the head plate using the guide pins (Figure 3E), add the screws, and tighten them by hand.
9. Seal the initially closed reactor with the help of, for example, a mechanical or hydraulic press (Figure 4A), far enough that the spring-loaded pressure pieces still have 2 mm of free space (Figure 4B). Then, tighten the screws by hand again (Figure 4C). Be aware that over-tightening can damage (bend) the multiclaves.
10. Place the multiclave in a programmable forced convection oven (Figure 4D), and then set and start the selected temperature-time program. It is advisable to use a convection oven to ensure uniform heating.
    1. For the discovery of Al-CAU-60, set the following temperature-time-program: Heat the oven to 160 °C in 12 h, maintain the target temperature for 36 h, and cool to room temperature (RT) in 12 h.
       NOTE: The choice of the temperature-time program can influence product formation³⁰. This includes the phases formed, but more often the crystal size and morphology³⁰.

3. Isolation and workup

1. Remove the multiclave from the oven when the temperature reaches room temperature.
2. Place the multiclave, for example, in a mechanical or hydraulic press and gently compress it until the screws can be loosened by hand (Figure 5A).
3. Place the multiclave in a fume hood and remove the head plate of the reactor, then remove the PTFE sheets and remove the sample plate with the PTFE inserts from the ground plate of the reactor (Figure 5B).
4. Inspect the PTFE inserts and check for crystals (Figure 5C). If present, isolate some of them together with some mother liquor.
5. Next, assemble the in-house high-throughput filtration block (Figure 6A): connect the filter block to a vacuum pump via two wash bottles, and place two filter papers between two silicone sealing mats with the corresponding recesses (Figure 6B-D) in the filter block. Place the PTFE filling block on top, making sure that the appropriate recesses match with the sealing mats and the filter block (Figure 6E). Tighten the layers using the clamping frame, which is held in place by four stud bolts. To properly seal the unit, use wing nuts on the stud bolts and tighten by hand (Figure 6F).
   NOTE: The technical drawings of the filtration block are shown in the supporting information (Supplementary File 3). If a filter block is not available, the products can also be filtered individually.
6. Close the recesses of the filling block that are not to be filled with plugs (Figure 6F).
   1. Later in the process, seal the recesses that have already been drained. This allows the other wells to be drained as well.
7. Turn on the membrane vacuum pump and set it to a mode in which it will pump down to the best possible vacuum (5-12 mbar).
8. Using disposable pipettes, transfer the contents of the PTFE inserts into the designated wells of the filling block (Figure 7A).
   NOTE: If harmful solvents (e.g., dimethylformamide ) are used, the products should be washed with ethanol or another less toxic and more volatile solvent to reduce contact with harmful substances during the following steps.
9. After all the inserts are empty, take a second look for crystals and isolate them if there are any (Figure 7B).NOTE: It is recommended to use an optical microscope with the possibility to use different magnifications in order to determine the size of the crystallites.
10. Carefully disassemble the filtration block once all the wells are drained (Figure 7C).
11. A so-called "product library" is now available on the filter paper (Figure 7D).
12. Dry the product library by allowing it to air-dry in a fume hood; in the case of non-toxic and non-corrosive solvents, the PXRD measurements can be performed with wet products.

4. Characterization

NOTE: For the discovery of new crystalline compounds, the products obtained are characterized by HT-PXRD. New crystalline phases are identified and used for further characterization. Working with the powder X-ray diffractometer follows a standard procedure, which can be found in the operating manual. A standard powder X-ray diffractometer can also be used, which makes the characterization more tedious.

1. Place the product library between two metal plates (base plate and cover plate; Figure 7E and Supplementary File 4) in a way that the recesses in the plates match the product locations to allow examination by PXRD. Carefully align the plates and secure them with two screws (Figure 7F).
2. Insert the product library into the sample holder of the diffractometer (Figure 8A,B).
   NOTE: Other sample holders may require different brackets. Refer to the user manual for further information.
3. Carefully place the loaded sample holder into the xy stage of the diffractometer and close the instrument (Figure 8C).
4. The diffractometer is controlled via WinX^POW software³¹. In the Diffractometer Control window, set the measuring mode by clicking on the Ranges menu and choose Scan Mode. A new window opens; herein, choose Scan Mode: Transmission, PSD Mode: Moving, Scan Type: 2Theta, and Omega Mode: Fixed and confirm the dialog.
5. To set the measuring parameters, click on the Ranges menu and choose Scan Range.
   1. A new window opens; herein, click on the Plus Icon and edit the appearing standard settings by double-clicking on it.
   2. To characterize the product library, perform a short 4 min measurement of each sample with the following settings: (a) 2Theta(Begin, End): 2, 47, (b) Step: 1.5, (c) Time/PSD Step [s]: 2, (d) Omega: 0. Confirm both dialogs.
6. To choose the samples to be measured on the xy stage, click on the Ranges menu and choose Scan Usage.
   1. A new window opens; herein, set the Scan Usage to Multiple Samples and check the option Individual Ranges/Files.
   2. Next, click on the button Ranges/Files; a new window ("HT_Editor") with 48 selectable sample positions opens. Select all positions with samples on the sample plate by clicking on the position with the 'control' key pressed.
   3. To activate the positions, use the right-click on Measure Samples. Confirm both dialogs.
7. Save the files by clicking on File in the menu and choose Save As. After choosing a directory and a filename, click on the Save button.
8. Start the measurement by clicking on Measure in the menu and choose the first entry, Data Collection. A new window opens; click on the Ok button to start the measurement.
   NOTE: The default settings and the procedure for calibrating the diffractometer should be taken from the user manual. The choice of measurement parameters (scanning angle, step size, time per scanning step) is also dependent on the density of the material, the weight of the diffracting atoms, etc., and may have to be adjusted. Absorption of the X-rays can be a problem if too much sample is formed and heavy elements are used.

5. Data evaluation

NOTE: An in-house procedure is used to evaluate the data; other procedures are conceivable. The PXRD data is obtained in ".raw" file format. To evaluate the diffractograms in other software, this file format must be converted, for example, to ".xyd" file format.

1. Open the WinX^POW software³¹. To open the powder X-ray diffractograms, use the Raw Data menu and choose Raw Data Handling. A new window opens.
2. Click on the icon for Batch Open and select all the files via Add Files. After selecting all the files, click on Open and confirm with Ok.
3. Normalize the intensities to a maximum value of 10,000 by clicking on the Ranges and choosing Adapt Intensities; a new window opens. Choose the option Normalize Intensities to max. Int. and write 10000. Click Ok.
   NOTE: WinX^POWsoftware³¹ overwrites the raw data when the data is changed; make sure to work on copies of the data.
4. Export the files via the Export icon in a file format suitable for evaluation programs. Choose an output directory and use the X/Y file format. Click Ok to finish the export.
5. Display the PXRD data in a stacked or separated view in a suitable program. Identify the most crystalline products by examining the number of reflections, half-widths (full width at half maximum [FWHM]), and signal-to-noise ratio.
   NOTE: For a first analysis, WinX^POWsoftware³¹ with the Graphics subroutine and the Search and Match function can also be used.

Results

The PXRD data is shown in Figure 9. For the first evaluation, the results obtained are linked to the synthesis parameters of the investigated parameter space. The investigation was carried out using six different molar ratios of linker to metal and four different molar ratios of NaOH/HCl to Al³⁺. By linking this information with the obtained PXRD data (Figure 9), it can be seen that products of low crystallinity were obtained from syntheses at a molar...

Discussion

Due to the complexity of the HT method, the individual steps and the method itself are discussed in the following sections. The first part covers the critical steps for each working step of the HT workflow (Figure 1), possible modifications, and limitations of the technique, where applicable. At the end, a general discussion also including the significance of the HT method with respect to existing methods and future applications is presented.

In the first step of...

Materials

Name	Company	Catalog Number	Comments
AlCl3·6H2O	Grüssing	N/A	99%
Filter block for filtration of max. 48 reaction mixtures	In-house made	N/A	Technical drawings in the supplementary files
Hydrochloric acid	Honeywell	258148	Conc. 37 %, p.a.
Multiclaves with 24 individual Teflon inserts	In-house made	N/A	Technical drawings in the supplementary files
N,N ‘-piperazine bis(methylenephosphonic acid	Prepared by coworkers	N/A	H4PMP,  Prepared by coworkers with the method reported by Villemin et al.: D. Villemin, B. Moreau, A. Elbilali, M.-A. Didi, M.’h. Kaid, P.-A. Jaffrès, Phosphorus Sulfur Silicon Relat. Elem. 2010, 185, 2511.
Sample Plate for PXRD	In-house made	N/A	Technical drawings in the supplementary files
Sodium hydroxide	Grüssing	N/A	99%
Stoe Stadi P Combi	STOE	Stadi P Combi	Cu-Kα1 radiation (λ = 1.5406 Å); transmission geometry; MYTHEN2 1K detector; opening angle 18°; curved  monochromator; xy-table
Forced convection oven	Memmert	UFP400