Nucleophilic aromatic substitution reactions under aqueous, mild conditions using polymeric additive HPMC

Borlinghaus, Niginia; Ansari, Tharique N.; Garrel, L.; Ogulu, Deborah; Handa, Sachin; Wittmann, Valentin; Braje, Wilfried M.

doi:10.1039/d1gc00128k

Cited by 23 publications

(19 citation statements)

References 41 publications

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“…Nucleophilic aromatic substitution reactions represent one of the most often used organic reactions in medicinal chemistry. − In collaboration with Abbvie, we recently explored the application of HPMC-derived hydrophobic pockets for S N Ar reactions under mild aqueous conditions without using any additives or cosolvents . The technology is compatible with various nucleophiles and has excellent functional group tolerance.…”

Section: Hpmc In Water Enables Extremely Short Reaction Timesmentioning

confidence: 89%

“…In contrast, in DMF, the reaction yields a 65:29:6 mixture of 4substituted, 2-substituted, and 2,4-disubstituted products, respectively. 33 Exceptional chemoselectivity was observed in nucleophiles containing boron, oxygen, nitrogen, and silicon atoms. N-arylation was preferred over O-arylation, which was utilized in a synthesis of dasatinib precursor 28.…”

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 91%

“…54−56 In collaboration with Abbvie, we recently explored the application of HPMC-derived hydrophobic pockets for S N Ar reactions under mild aqueous conditions without using any additives or cosolvents. 33 The technology is compatible with various nucleophiles and has excellent functional group tolerance. The optimized conditions employ inexpensive KOH or K 2 CO 3 as the base with equimolar amounts of other reagents.…”

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 99%

“…On the other hand, in DMF, 25% deborylation was observed. 33 The scalability was demonstrated by a 50 g scale reaction (33). The desired product was isolated in 96% yield without use of organic solvent at any stage.…”

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 99%

“…Recently, HPMC (hydroxypropyl methylcellulose), a cellulose-based additive, has also emerged as a significant enabler of chemistry in water through hydrophobic effects (Figure ). Although only a small number of reports on reactions in aqueous HPMC are available, − this technology has enormous potential, if it is further investigated and developed. Thus, this perspective focuses on aqueous HPMC as a sustainable reaction medium and reaction rate booster.…”

Section: Introductionmentioning

confidence: 99%

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HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

Sharma

Ansari

Handa

2021

ACS Sustainable Chem. Eng.

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The two types of water chemistries are (i) on water and (ii) in water. The fundamental understanding of "on water" chemistry is very well-known. In contrast, "in water" chemistry is yet not well understood. Micellar catalysis is a major enabler of "in water" chemistry, while HPMC (hydroxypropyl methylcellulose)-based chemistry is new and therefore underdeveloped. This perspective is dedicated to the in water chemistry of HPMC. Chemistry/catalysis in aqueous HPMC has recently been reported by AbbVie and our group. Using HPMC for "in water chemistry" requires a basic knowledge of the necessary procedures and limitations of this technology. Therefore, this perspective focuses on educating the audience about how HPMC can be effectively used in chemocatalysis. In addition, it includes how and why the viscosity of HPMC is a critical factor for the reaction’s success. We also list the viscosities of various grades of commercially available HPMC, so that readers can easily pick the supplier that provides the material of interest.

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Section: Hpmc In Water Enables Extremely Short Reaction Timesmentioning

confidence: 89%

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 91%

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 99%

Section: ■ Transformations In Aqueous Hpmcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

Sharma

Ansari

Handa

2021

ACS Sustainable Chem. Eng.

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Ultrasmall Cu^I Nanoparticles Stabilized on Surface of HPMC: An Efficient Catalyst for Fast and Organic Solvent‐Free Tandem Click Chemistry in Water

et al. 2022

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A simple and environmentally benign technology for synthesizing ultrasmall CuI nanoparticles (NPs) on the surface of the food additive hydroxypropyl methylcellulose (HPMC) and their application in completely organic solvent‐free tandem alkyne‐azide cycloaddition reactions were reported. The NP catalyst was thoroughly characterized by high‐angle annular dark‐field scanning transmission electron microscopy, high‐resolution transmission electron microscopy, energy‐dispersive X‐ray spectroscopy, and X‐ray photoelectron spectroscopy analysis for its morphology, particle size distribution, chemical composition, and oxidation state analyses. The NP catalyst was highly efficient, affording products in 10–45 min. All products were obtained in high purity by simple filtration, obviating organic solvents from the reaction set‐up to product isolation. The methodology is general and scalable as validated by a broad substrate scope.

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Application of an Oscillatory Plug Flow Reactor to Enable Scalable and Fast Reactions in Water Using a Biomass‐Based Polymeric Additive**

Hammer,

Nanto,

Canu

et al. 2023

ChemSusChem

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The utilization of water as a sustainable reaction medium has important advantages over traditional organic solvents. Hydroxypropyl methylcellulose has emerged as a biomass‐based polymeric additive that enables organic reactions in water through hydrophobic effects. However, such conditions imply slurries as reaction mixtures, where the efficacy of mass transfer and mixing decreases with increasing vessel size. In order to circumvent this limitation and establish an effectively scalable platform for performing hydroxypropyl methylcellulose‐mediated aqueous transformations, we utilized oscillatory plug flow reactors that feature a smart dimensioning design principle across different scales. Using nucleophilic aromatic substitutions as valuable model reactions, rapid parameter optimization was performed first in a small‐scale instrument having an internal channel volume of 5 mL. The optimal conditions were then directly transferred to a 15 mL reactor, achieving a three‐fold scale‐up without re‐optimizing any reaction parameters. By precisely fine‐tuning the oscillation parameters, the system achieved optimal homogeneous suspension of solids, preventing settling of particles and clogging of process channels. Ultimately, this resulted in a robust and scalable platform for performing multiphasic reactions under aqueous conditions.

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Nucleophilic aromatic substitution reactions under aqueous, mild conditions using polymeric additive HPMC

Abstract: The use of the inexpensive, benign, and sustainable polymer, hydroxypropyl methylcellulose (HPMC), in water enables nucleophilic aromatic subsitution (SNAr) reactions between various nucleophiles and electrophiles. The mild reaction conditions facilitate...

Cited by 23 publications

References 41 publications

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

Ultrasmall Cu^I Nanoparticles Stabilized on Surface of HPMC: An Efficient Catalyst for Fast and Organic Solvent‐Free Tandem Click Chemistry in Water

Application of an Oscillatory Plug Flow Reactor to Enable Scalable and Fast Reactions in Water Using a Biomass‐Based Polymeric Additive**

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Nucleophilic aromatic substitution reactions under aqueous, mild conditions using polymeric additive HPMC

Abstract: The use of the inexpensive, benign, and sustainable polymer, hydroxypropyl methylcellulose (HPMC), in water enables nucleophilic aromatic subsitution (SNAr) reactions between various nucleophiles and electrophiles. The mild reaction conditions facilitate...

Cited by 23 publications

References 41 publications

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

Ultrasmall CuI Nanoparticles Stabilized on Surface of HPMC: An Efficient Catalyst for Fast and Organic Solvent‐Free Tandem Click Chemistry in Water

Application of an Oscillatory Plug Flow Reactor to Enable Scalable and Fast Reactions in Water Using a Biomass‐Based Polymeric Additive**

Contact Info

Product

Resources

About

Ultrasmall Cu^I Nanoparticles Stabilized on Surface of HPMC: An Efficient Catalyst for Fast and Organic Solvent‐Free Tandem Click Chemistry in Water