(544ag) Continuous Ligand-Free Palladium-Mediated Carbon-Carbon Cross-Coupling | AIChE

(544ag) Continuous Ligand-Free Palladium-Mediated Carbon-Carbon Cross-Coupling


Bennett, J. - Presenter, North Carolina State University
Genzer, J., NC State University
Abolhasani, M., NC State University

Continuous Ligand-Free Palladium-Mediated
Carbon-Carbon Cross-Coupling

A. Bennett, Jan Genzer, and Milad Abolhasani


Transition metal-mediated
cross-coupling reactions offer organic chemists a range of stereo- and chemically-selective
reactions with extensive applications in fine chemical and pharmaceutical
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
alleviate some of these issues, a ligand-free heterogeneous catalysis reaction
was developed using palladium (Pd) loaded into a cross-linked 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)
instead of harsh and volatile organic solvents.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 microparticle
catalysts, 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

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 using
the Si-H functionality present on the PHMS backbones. After the reduction, the
Pd-loaded particles can be washed and dried for long-term 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.

Figure 1. TEM images of bulk
cross-section of Pd-loaded catalyst microparticles with unloaded control.

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).
Reaction yield was determined on collected effluent samples using high
performance liquid chromatography (HPLC) with naphthalene as an internal

Reaction Scheme 1. Generalized Suzuki-Miyaura cross-coupling.
1). Oxidative addition 2). Base-Halide substitution 3). Transmetalation 4).
Reductive Elimination.  Aryl Halide (R-X), arylboronic acid (R-B(OH)2),
and base (M+A-).

Figure 3.A). µ-PBR packing
in 1/8’’ OD FEP tubing. Scale bar is 200 µm and B). Reaction time series of
HPLC elution traces. Reaction Conditions: 10 min residence time, temperature=65°C,
4-iodotoluene (0.2 M), naphthalene (0.05 M), phenylboronic acid (0.3 M), and potassium
carbonate (1M).

Figure 4. A). Reaction
yield vs. time startup curves for the µ-PBR and B). Steady-State reaction
yields vs. bed residence time.

Further work on examining this continuous synthesis method
and heterogeneous catalyst is underway involving a broad array of substrates
and modifications to the catalyst particles is ongoing to optimize the catalyst
and reaction.

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.

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

       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.

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

       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.

       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.