(731i) Monodisperse Elastomeric Microparticle Scaffolds for Heterogeneous Palladium-Mediated Catalysis

Authors: 
Bennett, J. A., North Carolina State University
Abolhasani, M., North Carolina State University
Genzer, J., NC State University

Monodisperse
Elastomeric Microparticle Scaffolds for Heterogeneous Palladium-Mediated
Catalysis

Jeffrey
A. Bennett, Jan Genzer, and Milad Abolhasani

 

Metal-mediated
cross-coupling reactions offer organic chemists a wide array of stereo- and chemically-selective
reactions with broad applications in fine chemical and pharmaceutical synthesis.1
Current batch-based synthesis methods are beginning to be replaced with flow
chemistry strategies to take advantage of the improved consistency and process
control methods offered by continuous flow systems.2,3
Most cross-coupling chemistries still encounter several issues in flow using
homogeneous catalysis, including expensive catalyst recovery and air
sensitivity due to the chemical nature of the catalyst ligands.1 To
mitigate some of these issues, a ligand-free heterogeneous catalysis reaction
was developed using palladium (Pd) loaded into a polymeric network of a
silicone elastomer, poly(hydromethylsiloxane) (PHMS), that is not air sensitive
and can be used with mild reaction solvents (ethanol and water).4

In this work we present a
novel method of producing soft catalytic microparticles using a multiphase
flow-focusing microreactor and demonstrate their application for continuous Suzuki-Miyaura
cross-coupling reactions. The catalytic microparticles are produced in a
coaxial glass capillary-based 3D flow-focusing microreactor. The microreactor
consists of two precursors, a cross-linking catalyst in toluene and a mixture
of the PHMS polymer and a divinyl cross-linker. The dispersed phase containing
the polymer, cross-linker, and cross-linking catalyst is continuously mixed and
then formed into microdroplets by the continuous phase of water and surfactant
(sodium dodecyl sulfate) introduced in a counter-flow configuration. Elastomeric
microdroplets with a diameter ranging between 50 to 300 micron are produced at
25 to 250 Hz with a size polydispersity less than 3% in single stream
production. The physicochemical properties of the elastomeric microparticles
such as particle swelling/softness can be tuned using the ratio of cross-linker
to polymer as well as the ratio of polymer mixture to solvent during the
particle formation. Swelling in toluene can be tuned up to 400% of the initial
particle volume by reducing the concentration of cross-linker in the mixture
and increasing the ratio of polymer to solvent during production.5

After the particles are
produced and collected, they are transferred into toluene containing palladium
acetate, allowing the particles to incorporate the palladium into the polymer
network and then reduce the palladium to Pd0 with the Si-H
functionality present on the PHMS backbones. After the reduction, the Pd-loaded
particles can be washed and dried for storage or switched into an ethanol/water
solution for loading into a micro-packed bed reactor (µ-PBR) for continuous organic
synthesis. The in-situ reduction of Pd within the PHMS microparticles was
confirmed using energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron
spectroscopy (XPS) and focused ion beam-SEM, and TEM techniques.

In the next step, we used
the developed µ-PBR to conduct continuous organic synthesis of 4-phenyltoluene
by Suzuki-Miyaura cross-coupling of 4-iodotoluene and phenylboronic acid using
potassium carbonate as the base. Catalyst leaching was determined to only occur
at sub ppm concentrations even at high solvent flow rates after 24 h of
continuous run using inductively coupled plasma mass spectrometry (ICP-MS).

The developed µ-PBR using
the elastomeric microparticles is an important initial step towards the
development of highly-efficient and green continuous manufacturing technologies
in the pharma industry.
In addition, the developed elastomeric microparticle synthesis technique can be
utilized for the development of a library of other chemically cross-linkable polymer/cross-linker
pairs for applications in organic synthesis, targeted drug delivery, cell encapsulation,
or biomedical imaging.

Graphical Abstract:

 

References:

1.        Ruiz-Castillo P, Buchwald
SL. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem
Rev
. 2016;116(19):12564-12649. doi:10.1021/acs.chemrev.6b00512.

2.
       Adamo A, Beingessner RL, Behnam M, et al. On-demand continuous-flow
production of pharmaceuticals in a compact, reconfigurable system. Science.
2016;352(6281):61 LP-67.
http://science.sciencemag.org/content/352/6281/61.abstract.

3.
       Jensen KF. Flow Chemistry — Microreaction Technology Comes of Age.
2017;63(3). doi:10.1002/aic.

4.
       Stibingerova I, Voltrova S, Kocova S, Lindale M, Srogl J. Modular
Approach to Heterogenous Catalysis. Manipulation of Cross-Coupling Catalyst
Activity. Org Lett. 2016;18(2):312-315. doi:10.1021/acs.orglett.5b03480.

5.
       Bennett JA, Kristof AJ, Vasudevan V, Genzer J, Srogl J, Abolhasani M.
Microfluidic synthesis of elastomeric microparticles: A case study in catalysis
of palladium-mediated cross-coupling. AIChE J. 2018;0(0):1-10. doi:10.1002/aic.16119.