# 7 Résumé

Matthias Kraume

This volume presents the results obtained in the DFG Collaborative Research Center/ Transregio 63 integrated chemical processes in liquid multiphase systems between 2010 and 2022. The overarching objectives of the research were a better understanding, detailed modeling, technical realization, and optimal design of liquid multiphase systems for the homogeneously catalyzed conversion of long-chain molecules. Substrates such as dodecene and unsaturated oleochemicals were selected to mimic biogenic feedstocks that are expected to increasingly replace conventional petrochemicals as raw materials in the near future. The physical properties of long-chain molecules call for specific solutions for an efficient contact between the reacting components and the catalysts used, as well as efficient separation of products, feeds, and catalysts to recycle the expensive catalysts and unconverted feedstock. To optimally meet the conflicting requirements of the chemical reaction and the subsequent separation steps, multiphase systems are a very promising option. Hydroformylation, hydroesterification, and hydroaminomethylation were selected as model reactions because they exhibit specific properties of industrially relevant reactions.

To use such unconventional multiphase systems in as environmentally friendly as possible processes, an innovative path that has not yet been implemented industrially was pursued: using phase systems with partially tunable properties. Three different phase systems (thermomorphic multiphase systems (TMS), microemulsion systems (MES), and Pickering emulsions (PE)) were selected from several possible options, as they represent a broad spectrum from highly dispersed and switchable to stable and easily separable. In these systems, different additives transform the originally nearly immiscible phases that contain the catalysts on the one hand and the reactants on the other into well-dispersed systems that provide the required contact between them, enabling fast chemical reactions by improved mass transport. The advantages of homogeneous catalysis were utilized while minimizing the problems usually associated with it, namely the recovery and recycling of the highly efficient but generally very expensive catalyst complexes.

The research on the example processes covered all levels of chemical process development, from the elementary steps of the reaction and the interaction with the reaction medium, the characterization of the investigated phase systems to the design and optimization of the individual processing steps to the design and operation of entire plants on the miniplant scale. Besides process and systems technology, investigations of physicochemical fundamentals constituted the scientific backbone of the research.

The thermodynamic and chemical fundamentals, as well as mass transfer phenomena, were elucidated and quantified as a preliminary step of process development and operation for the investigated phase systems. The determination of thermodynamic

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<footnote>Open Access. © 2022 Matthias Kraume, published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License.</footnote>
data for process design usually requires a high experimental effort. Therefore, signifi-
cant attention was paid to increasing the predictive power of the thermodynamic mod-
els. Two physically based models, the perturbed-chain statistical associating fluid
theory (PC-SAFT) and the lattice cluster theory (LCT), were applied and complemented
by new approaches developed for the description of TMS. As a result, both thermody-
namic models could describe the phase equilibria of the studied TMS mixtures with an
excellent agreement with the experimental data.

Regarding PC-SAFT, a new heterosegmented approach led to noticeable im-
provements in the prediction power. Furthermore, some model parameters could be
correlated with the number of carbon atoms within a homologous series of mole-
cules. Regarding LCT, an improvement in the description of small molecules could
be achieved. Besides the phase behavior, the interfacial properties, such as interfa-
cial tension, surface tension, and adsorption isotherms, could be modeled in good
agreement with experimental data. This predictive power was achieved by combin-
ing the thermodynamic models with the density functional theory (DFT) for inho-
mogeneous systems. Additionally, PC-SAFT was also used to investigate chemical
reactions. Precisely, the impact of solvents on the reaction equilibrium could be
predicted in excellent agreement with experimental findings.

The phase behavior of mixtures that contain surfactants cannot be modeled in
full detail because nanostructures are formed. Therefore, for mixtures containing sur-
factants, experimental investigations were performed that led to reliable phase dia-
grams. In addition, the aggregation model could be improved by replacing empirical
correlations with PC-SAFT in combination with density gradient theory (DGT).

Due to the importance of reaction kinetics for reactor design and optimization, a
general strategy was developed for deriving and parametrizing mechanistically based
kinetic models for reactions in multiphase systems. This methodical approach is based
on detailed catalytic cycles and their subsequent simplification utilizing different re-
duction approaches. To provide a deeper understanding of such complex reaction
mechanisms and reaction networks, an interdisciplinary collaboration of chemistry,
thermodynamics, quantum mechanics, and reaction engineering was required, both
theoretically and experimentally. The developed method was successfully applied to
the Rh/BIPHEPHOS-catalyzed isomerizing hydroformylation of 1-decene and isomeric
feed mixtures consisting of re-isomerization and subsequent hydroformylation. Consid-
ering a complex reaction network of isomerization, hydrogenation, and hydroformyla-
tion, an excellent match between simulated and experimental data was achieved in a
broad range of operating conditions using a single set of kinetic parameters.

In liquid multiphase systems, incompletely miscible organic and aqueous phases
are brought into contact for a chemical reaction. In addition, gaseous feed compo-
nents often occur, for example, in hydroformylation. In phase systems with partially
tunable properties, this leads to complex mass transport phenomena which had not
been described before. Therefore, the liquid-liquid and the gas-liquid mass transfer
were characterized for the three different phase systems experimentally using different
devices. In addition to material properties such as diffusion coefficients and operating conditions, in particular fluid dynamics and temperature, the composition of the phase systems influences the transfer rates in a complex manner.

Complete processes for all three investigated phase systems were developed and successfully demonstrated based on the thermodynamic models and reaction kinetics. These processes include the chemical reaction, a phase separation step, and catalyst recovery and recycling in an integrated manner.

All three investigated phase systems were shown in the literature to be suitable for various chemical reactions using soluble catalysts, either typical homogeneous catalysts like metal complexes or enzymes. For all phase systems, detailed knowledge of their thermodynamics, separability, and physical properties was the basis for establishing a suitable phase separation that enables recycling of the catalysts and isolation of the products. Each phase system has its own advantages and disadvantages, rendering them the best-suited choice for different reactions and tasks. A broad range of additives is available for all phase systems, providing enough freedom to formulate appropriate reaction media for various chemical reactions with many different catalysts. MES and PE require only small amounts of additives, while TMS utilize larger quantities. On the other hand, water as the solvent for the catalyst requires a highly hydrophilic ligand. Still, water completely avoids the utilization of organic solvents, opening an optimal approach to Green Chemistry. Challenges in phase separation and catalyst recycling that had so far limited a more comprehensive application of the three phase systems were overcome, thus paving the way for continuous operation. Decantation (TMS and MES) was combined with other unit operations such as organic solvent nanofiltration for improved recycling of catalyst and additives and the removal of by-products. The combination of PE with membrane filtration has been shown to be a very promising and robust technique for efficient catalyst and additives recycling in a single step. For both MES and PE, models that describe the separation accurately were developed and can be used for model-based optimization and control of such processes.

For the example of the hydroformylation of 1-dodecene with modified rhodium catalysts, experimental investigations were carried out with TMS and MES in miniplant runs over several days using a CSTR as the reactor, continuous phase separation, catalyst phase recycling, and product withdrawal. The experiments in PE were performed as repeated batch runs. Although continuous phase separation and catalyst retention were achieved, catalyst recycling was not realized yet for hydroformylation in PE. The *n*-iso selectivity and the selectivity toward aldehydes were comparable in all three phase systems. Due to the different applied catalysts, the observed difference in reaction performance is probably caused by the inherently less active Rh/XANTPHOS catalyst compared to Rh/BIPHEPHOS rather than by the type of phase system. Lower reaction yields of a phase system can be outweighed by the ease of separation in an overall economic optimization of the entire integrated process. The achieved results demonstrate the feasibility of applying all three systems as reaction media for the
homogeneously catalyzed conversion of hydrophobic substrates, including efficient
catalyst recycling.

The selection of a multiphase system as a reaction medium is motivated by the
advantages for facilitated product isolation and catalyst separation and recycling.
However, compared to a single solvent, such systems introduce substantial com-
plexity into the development process. Their selection and design require detailed
knowledge of the thermodynamics of nonideal liquid mixtures or the surface activ-
ity of surfactants or particles in combination with their colloidal properties. For the
separation, often additional nonstandard unit operations and advanced control pro-
cedures are required. This introduces additional complexity and design degrees of
freedom into the development process, requiring the best possible combination of
experimental work with modeling, simulation, and optimization.

A significant challenge in designing a chemical production process is that the
real production process consists of several unit operations involving various pieces of
equipment, usually including recycle streams. This complexity makes it challenging
to make the right decisions based only on experimental work, basic mathematical
models for reaction kinetics and thermodynamics, and prior experience. However,
computer and model-based (or systems engineering) methods can efficiently support
this complex decision process. In this research project, a toolkit was developed for
this decision support and successfully demonstrated for multiphase processes.

As a first step in the systematic design of integrated processes, models of the
different process steps are set up that include detailed models of the underlying
phenomena and processes. These models can be incorporated into a stationary or
dynamic flowsheet simulation of the overall process. To support this step, an inte-
grated environment for transparent and collaborative process modeling was devel-
oped that facilitates combining different submodels and supports the automatic
translation of the overall model into code that commercial simulation packages can
run. Additionally, detailed fluid dynamics models of critical processing units for
multiphase processes were developed, which are necessary to investigate the per-
formance and the influence of the operational parameters on their performance.
When complex thermodynamic models are used for simulation and optimization,
this may lead to unacceptably long computation times due to the iterative solution
of the model equations. Approximating the result from these models by surrogate
models, that is, mathematical structures that can faithfully represent arbitrary
input-output data, was shown to be efficient in solving this issue.

The scope of using optimization methods to explore the entire design space for
process development was extended in several directions. The optimization of reac-
tors based on the elementary process function methodology showed significant im-
provements over heuristically found solutions as demonstrated by experimental
validation for the hydroformylation of 1-dodecene in a TMS. Global optimization
methods for superstructures that involve discrete decision variables were developed
and successfully applied to several examples of liquid multiphase processes. In the
early stages of the design process, the model parameters often can only be deter-
mined with limited accuracy. To deal with these uncertainties, an approach was de-
veloped which distinguishes between design degrees of freedom that have to be
fixed when a plant is built and operational degrees of freedom that later are
adapted to the real behavior in the best possible fashion. Finally, advanced con-
trol and real-time optimization techniques were developed for and demonstrated
at the miniplants and pilot plants. So, the plants could be operated optimally,
thus providing reliable information for assessing the potential of the different
phase systems, catalyst systems, and plant designs.

The methods used here for process design require sufficiently accurate models
of the different elements of the investigated production process. It was demon-
strated that models with high predictive quality could be derived for such complex
processes. These models were successfully used in the operation of plants at the
miniplant and pilot plant scale. However, this comes at a price: model development
and validation are costly and time-consuming processes requiring expert knowl-
edge. Hence, the effort for model building should ideally focus on the most promis-
ing options, but determining these options systematically involves the availability
of models of sufficient predictive capability. To overcome this contradiction, itera-
tive development processes consisting of (ideally model-based) screening of alter-
natives, initial experimental work, model building, model-based optimization,
design of new experiments, further model refinement, optimization with reduced
uncertainty, additional experiments, and so on up to the validation of a small num-
ber of remaining options at miniplant or pilot plant scale are needed.

Therefore, workflows to integrate the methods for process design along the
chemical process development pathway were developed with a particular focus on
processes with liquid multiphase systems. Vital elements for integrated process de-
sign are general selection criteria for multiphase systems suitable for the given tar-
get products or reactions. A methodology was established that allows quantitative
comparison of various types of phase systems during different process design
stages, without the need for extensive experts' knowledge. The complexity of the
considered phase systems is reduced by the systematic application of question-
naires and key experiments. The whole procedure was cast into the modular com-
puter-aided phase system selection (caPSS) framework, which integrates several
essential aspects of process development: data acquisition, model generation, con-
ceptual process design, flowsheet optimization, and evaluation regarding economic
feasibility as well as Green Chemistry criteria.

For TMS, the choice of solvents in which a specific homogeneously catalyzed
reaction proceeds with both a high reaction rate and a high selectivity is crucial.
Different approaches were derived from quantum chemistry and thermodynamics
to support the identification of suitable solvents. Screening of chemical equilibria
or transition state barriers as a function of solvent polarizability provides insights
into the reaction thermodynamics and kinetics. The developed methodologies are
well suited to generate a set of potential solvent candidates that are combined with other solvents to obtain mixtures featuring a TMS behavior.

Integrated process development requires the combination of solvent design and process design. Usually, these two design tasks are performed sequentially. While computer-aided molecular design (CAMD) can aid in selecting solvents that possess process-relevant solvent properties, only the simultaneous consideration of solvent and process design in an integrated computer-aided molecular and process design (CAMPD) framework ensures the identification of optimal process designs and operation points. Examples illustrated key aspects in CAMD/CAMPD. Nonetheless, experimental validation is still required due to uncertainties and possible unforeseen chemical effects.

According to the caPSS framework, one of the essential integration steps is the combination of phase system selection with model-based process synthesis. For this purpose, an integrated model-based process design methodology was developed, combining both aspects, using various sources of knowledge. The methodology involves an iterative workflow wherein suitable models are identified and calibrated before evaluating the final process design regarding reaction and separation performance, sustainability, and economic potential. In the case of high levels of uncertainty, model-based optimal experimental design was used to improve the available data basis successively via carefully designed experiments. As a result, critical model parameters can be identified with minimal experimental effort.

Overall, the research program of the SFB/TR 63 resulted in an elaborated, integrated toolkit for the rapid development of liquid multiphase processes. The work has significantly advanced the technology readiness level of each of the three phase systems. All steps in process design, starting from the first theoretical concept to the overall process selection, process simulation, and optimization, were covered. Numerous methodological innovations were proposed, tested, and validated using the representative sample reactions. The whole development chain from the first reaction-related investigations in the laboratory up to the technological realization in automatically controlled miniplants and pilot plants was implemented. Based on the experiences gained during the entire duration of the SFB/TR 63, a classification was developed for an efficient selection of a suitable phase system for a broad spectrum of homogeneously catalyzed reactions based on carefully selected key experiments and the assessment of fundamental properties of substances and mixtures.

Even after 12 years of research, it also became clear that, as in every scientific project, more research is still necessary to validate and extend the derived knowledge base. In general, the various methods should be applied and checked for other reactions and especially different phase systems. Models must be tested for their accuracy and possibly sharpened. The tools for systems engineering and integrated
process design should be applied for other practical examples. So, the selection
criteria for liquid multiphase systems must be further tested. Finally, methodologies
like model-based process development still need to be extended. However, all meth-
ods developed in this collaborative program may pave the way for a more sustainable
chemical production in the future based on liquid multiphase processes.
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