Organocatalysis in continuous flow

S.A. van den Berg

Research output: Thesisinternal PhD, WU

Abstract

Continuous flow chemistry is an enabling technique in organic chemistry. Advantages include extremely fast mixing and heat transfer capabilities as well as rapid screening of reaction conditions. Combining continuous flow chemistry with solid-supported organocatalysis presents challenges that have been investigated in this thesis.

We have developed a technique to modify the surface of silicon carbide with alkenes using microwaves. Silicon carbide is an extremely tough bio-compatible material and is of interest as a solid support. By using monolayers of bifunctional alkenes we were able to perform follow-up reactions to attach other molecules of interest, thereby further modifying the surface chemistry of silicon carbide. The use of microwaves speeds up the attachment of monolayers by as much as sixteen times.

We have developed a new method for the surface functionalization of MCM-41, a type of mesoporous silica. Mesoporous silica is an interesting solid support for catalysts because of its large surface area. 1,7-octadiene can be covalently attached under mild conditions (24 h, 100 ºC). Follow-up thiol-ene click reactions can be performed using thiols. The use of 1,2-ethanedithiol leads to a material that can be reacted with the organocatalyst quinine, giving catalytically active mesoporous silica. This material was tested in flow and yielded full conversion of starting materials for the thio-Michael addition of 3-methoxythiophenol and 1-cyclohex-2-enone.

Sulfonic acid supported on mesoporous silica (SBA-15) made via co-condensation of a thiol-containing silica precursor was used in a packed-bed continuous flow setup. This solid-supported sulfonic acid efficiently catalyzes the protection and deprotection of various alcohols as the tetrahydropyranyl-, trimethylsilyl and dimethylphenylsilyl derivatives under continuous flow conditions. By passing the starting material (primary, secondary, benzylic and phenolic alcohols) together with the appropriate protecting group over the packed bed more than 100 mg of product was produced in flow.

Finally, the ring-opening polymerization of L-lactide using an organocatalyst was investigated. Using low catalyst loading and short residence times (0.25– 1.2% TBD catalyst, residence times as short as 2 s) well-defined poly(lactic acid) (PLA) is obtained with high (95–100%) monomer conversions and PDIs of typically 1.2. Use of the microreactor allows for a rapid screening of optimal reaction conditions, consistently yielding the optimal values for high conversion and low polydispersity. This quickly revealed that longer residence times will give rise to higher conversions and a concomitantly broader molecular weight distribution due to transesterification of the polymer backbone by TBD.

The organocatalytic, metal-free continuous flow method described is rapid and mild enough to allow the use of a PEG-5,000 macroinitiator (yielding block copolymers), exo-BCN alcohol and even a base-labile tetrazine-derived alcohol, the latter of which cannot be used under traditional batch conditions. The resulting BCN-PLA and tetrazine-PLA materials were readily functionalized with small molecules and large polymers bearing azides and norbornenes via SPAAC and inverse electron demand Diels-Alder click chemistry.

Despite the challenges that arise, the combination of continuous flow chemistry and (solid-supported) organocatalysis is a powerful concept that warrants further investigation.

 

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • Zuilhof, Han, Promotor
  • Wennekes, Tom, Co-promotor
Award date1 Apr 2016
Place of PublicationWageningen
Publisher
Print ISBNs9789462576636
Publication statusPublished - 2016

Keywords

  • catalysis
  • organic chemistry
  • flow
  • microfluidics
  • alkenes

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