Continuous Flow Chemistry: Reaction of Diphenyldiazomethane with p-Nitrobenzoic Acid

Summary

Flow chemistry carries environmental and economic advantages by leveraging superior mixing, heat transfer and cost benefits. Herein, we provide a blueprint to transfer chemical processes from batch to flow mode. The reaction of diphenyldiazomethane (DDM) with p-nitrobenzoic acid, conducted in batch and flow, was chosen for proof of concept.

Abstract

Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer and cost savings through the "scaling out" strategy as opposed to the traditional "scaling up". Herein, we report the reaction of diphenyldiazomethane with p-nitrobenzoic acid in both batch and flow modes. To effectively transfer the reaction from batch to flow mode, it is essential to first conduct the reaction in batch. As a consequence, the reaction of diphenyldiazomethane was first studied in batch as a function of temperature, reaction time, and concentration to obtain kinetic information and process parameters. The glass flow reactor set-up is described and combines two types of reaction modules with "mixing" and "linear" microstructures. Finally, the reaction of diphenyldiazomethane with p-nitrobenzoic acid was successfully conducted in the flow reactor, with up to 95% conversion of the diphenyldiazomethane in 11 min. This proof of concept reaction aims to provide insight for scientists to consider flow technology's competitiveness, sustainability, and versatility in their research.

Introduction

Green chemistry and engineering are creating a culture change for the future direction of industry^1,2,3,4. Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer, and cost savings through the "scaling out" strategy as opposed to the traditional "scaling up"^{5,6,7,8,9....}

Protocol

Health Warnings and Specification of Reagents
Benzophenone Hydrazone: May cause irritation of the digestive tract. The toxicological properties of this substance have not been fully investigated. May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated. May cause skin irritation and eye irritation¹⁸.

Activated manganese oxide (MnO₂): (Health MSDS rating of 2) Hazardous in case of skin contact, eye contact, ingestion, and inhalation¹⁹.

Dibasic potassium phosphate (KH_....

Results

Batch Reaction
Diphenyldiazomethane was prepared according to literature^28,29. The compound was crystallized from petroleum ether:ethyl acetate (100:2) and the purple crystalline solid was analyzed by H¹ NMR, melting point, and MS. The analyses were consistent with the structure and reported literature values.

The reaction of diphenyldiazo.......

Discussion

Flow chemistry has gained much attention recently with an average of about 1,500 publications on the topic annually in research areas of Chemistry (29%) and Engineering (25%). Many successful processes have been conducted in flow. In numerous cases, flow chemistry was demonstrated to exhibit superior performances to batch for many applications such as the preparations of pharmaceutically active ingredients^30,31, natural products³², and spe.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Thermometer	HB-USA/ Enviro-safe		Any other instrument scientific company provider works
Benzophenone hydrazone	Sigma-Aldrich		Store at 2-8 °C, 96% purity
Activated MnO2	Fluka		≥ 90% purity, harmful if inhaled or swallowed. Refer to MSDS for more safety precautions
Dibasic KH2PO4	Sigma-Aldrich		Serious eye damage, respiratory irritant. Refer to MSDS for more safety precautions
Dichloromethane (DCM)	Alfa Aesar		≥ 99.7% purity, argon packed
Rotovap	Büchi		accessory parts include Welch self-cleaning dry vacuum model 2027, and Neuberger KNP dry ice trap
Bump trap	Chemglass		Any other instrument scientific company provider works
Neutral Silica Gel (50-200 mM)	Acros Organic/ Sorbent Technology		Respiratory irritant if inhaled, refer to MSDS for more safety precautions
Inert Argon Gas	Airgas		Always ensure proper regulator is in place before using
Medium Porosity Sintered Funnel Glass Filter	Sigma-Aldrich		Any other instrument scientific company provider works
Aluminum Foil	Reynolds Wrap		Any other company works. Used to prevent photolytic damage towards DDM
Para-NO2 benzoic acid	Sigma-Aldrich		Skin contact irritant, eye irritant, respiratory irritant. Refer to MSDS for more safety precautions
Pure ethyl alcohol (200 proof)	Sigma-Aldrich		≥ 99.5% purity, anhydrous. Highly flammable
Toluene	Sigma-Aldrich		≥ 99.8% purity, anhydrous. Skin permeator, flammable
Ortho-xylene	Sigma-Aldrich		99% purity, anhydrous. Toxic to organs and CNS. Adhere to specifications dictated within MSDS
Diphenyl diazo methane	Produced in-house		Respiratory irritant, refer to MSDS for more safety precautions
Corning reactor	Corning Proprietary		Manufactured in 2009. model number MR 09-083-1A
Stop watch	Traceable Calibration Control Company		Any other company that provides monitoring with laboratory grade accredidation works
Analytical balance	Denver Instruments		Model M-2201, or any analytical balance that has sub-milligram capabilities
Dram vials	VWR		2 dram, 4 dram, and 6 dram vials
Micropipettes	Eppendorf		2-20 μL and 100-1000 μL micropipettes work
Glass pipettes	VWR		Any other instrument scientific company provider works
GC-MS	Shimadzu GC		Software associated: GC Real Time Analysis
GC vials	VWR		Any other providing company works
Beakers	Pyrex		500 mL beakers
Syringe pumps	Sigma Aldrich		Teledyne Isco Model 500D
Relief valve	Swagelok		Spring loaded relieve valve
One-way valves	Nupro		10 psi grade
Two-way straight valves	HiP		15,000 psi grade