Flow chemistry diazomethane reaction

Diazomethane (CH₂N₂) is an extremely important reagent in organic synthesis.  Its unique molecular structure consists of a linear arrangement of one carbon atom connected to two nitrogen atoms (N≡N⁺-CH₂⁻). This structure gives it dual reactivity:

(1) As a strong methylating agent: Diazomethane is a highly reactive methylating agent that can provide methyl groups to carboxylic acids, phenols, enols, etc.

(2) As a 1,3-dipole: It can participate in various cycloaddition reactions to form heterocyclic compounds.

Diazomethane is the most reactive and simplest methylating, cyclopropanating, and homologating reagent in C1 chemistry. It can convert acids to esters, alcohols to methyl ethers, olefins to cyclopropanes, and acyl chlorides to α-diazoketones under mild conditions, and is widely used in pharmaceutical intermediates, total synthesis of natural products, and radioactive ¹¹C/¹⁴C labeling. However, its boiling point is only -23 ℃, and in liquid or high concentrations, it is extremely prone to violent exothermic decomposition (ΔH≈-340 kJ mol⁻¹) due to heat, friction, metal impurities, or local overheating; contact with alkali metal ions on the glass surface can cause deflagration. Traditional "in-situ dropwise addition-low-temperature distillation" processes are limited to gram-scale operations and require large amounts of diethyl ether as an azeotropic agent.  A leak can easily form an explosive mixture of diazomethane and oxygen. Microreactors, due to their small channel size, low liquid holdup, rapid heat transfer, and large surface-to-volume ratio, can control the single-pass online quantity to <50 mg, thus reducing "macro-scale explosions" to "micro-scale leaks," providing an inherently safe premise for continuous and scaled-up production.

Ferstl et al. (2008, DECHEMA) first used an IMM micromixer coupled with a PTFE capillary (ID = 0.5 mm, V = 17.8 mL) for the continuous generation of diazomethane: a solution of N-methyl-N-nitrosourea (MNU) in MTBE was reacted with a 0.93 M KOH aqueous solution at 10 °C with a residence time of 5-30 s, followed by quenching with benzoic acid to yield methyl benzoate. The CH₂N₂ generation rate was determined by tracking the ester yield using online HPLC.  It was found that when MNU/KOH = 1:1.5 and the total flow rate was 1 mL min⁻¹, the yield reached 92% within 60 s; whereas the traditional semi-batch process required 2 hours and only achieved a yield of 70%.

Safety assessment: In an adiabatic calorimeter, the decomposition of MNU started at only 36 °C, with an adiabatic temperature rise ΔTad ≈ 240 K; however, due to instantaneous heat transfer in the microchannel, the measured temperature rise was <2 °C, confirming that "hot spots" were effectively controlled.

To avoid the explosive and carcinogenic properties of MNU, Strümpel et al. (2010) used commercially available Diazald (N-methyl-N-nitrosotoluene-p-sulfonamide) as a precursor. Although it is highly irritating to the eyes and skin, its impact sensitivity is >40 J, classifying it as a non-explosive substance. In an LTF ST-3-1 micromixer (with interdigitated internal components), a solution of Diazald in DMF/isopropanol reacted with 2M KOH at 0-50 ℃ with a residence time of 20-60 s to produce CH₂N₂, which was then quenched with benzoic acid.  After continuous operation for 1 hour, the yield of methyl benzoate was 75%, an increase of 25 percentage points compared to the batch method. The authors systematically compared the "capillary vs. micromixer" modes and found that the micromixer, due to its segmented-recombined flow field, increased the mass transfer coefficient kL by three times, eliminating the sensitive dependence on residence time and demonstrating the advantage of microreactors being "mass transfer dominated" rather than "kinetically limited."

Maurya et al. (2012, Adv. Synth. Catal.) proposed a PDMS dual-channel microreactor, separating the upper and lower liquid flows with a 45 μm hydrophobic PDMS membrane: the lower channel contained an aqueous solution of Diazald/KOH, and the upper channel contained the substrate (benzoic acid, styrene, p-chlorobenzoyl chloride, etc.) dissolved in DMF. CH₂N₂ was generated on the alkaline side and immediately reacted after diffusing through the membrane into the organic side. The diffusion flux of CH₂N₂ across the membrane was approximately 2×10⁻⁸ mol cm⁻² s⁻¹, with a separation efficiency of 63%. This design cleverly confines the "hazardous substance" to one side of the membrane, with only the substrate and product on the other side, eliminating the gas phase and thus the risk of explosion. The water-sensitive Arndt-Eistert reaction (acyl chloride → α-diazoketone → Wolff rearrangement to the homologous ester) could also be carried out in the microreactor, with 72 hours of continuous operation without membrane wetting or clogging, achieving a daily yield of 2.9 mmol, a 60% reduction in reaction time compared to the traditional two-step batch process.

Rossi et al. (2012, Org. Process Res. Dev.), in collaboration with Corning, scaled up the above process to 19 mol day⁻¹ using a Corning Advanced-Flow™ "heart-shaped" glass microreactor (channel depth = 600 μm, width = 1 cm, V = 25 mL). Scaling was achieved through numbering-up (10 modules in parallel) rather than size scaling, maintaining constant channel dimensions to ensure linear scaling of heat and mass transfer performance. Key process parameters: MNU (0.45M)/KOH (0.6M) = 1:1.3, total flow rate 33 mL min⁻¹, residence time 34 s, quenching agent benzoic acid 3 eq. The average yield over long-term operation (90 hours) was 90%, with a single-pass online diazomethane quantity of <0.4 g, meeting the US Process Safety Management (PSM) exemption threshold for "low hazard inventory." This demonstration was certified as an "inherently safe" process by the German Technical Inspection Association (TÜV), providing a regulatory basis for subsequent industrial implementation.

(1) Cyclopropanation: Ferstl dissolved Pd(acac)₂ (1 mol%) in styrene and reacted it with CH₂N₂ generated from MNU/KOH at 10 °C for 60 seconds. The styrene conversion rate was >99%, and the cyclopropylbenzene yield was 92%; while the batch method required -20 °C and 2 hours, with a yield of only 65%.

(2) Pyrazole and pyrrole synthesis: Diazomethane undergoes 1,3-dipolar cycloaddition with α,β-unsaturated ketones. 3-Methylpyrazole can be obtained in 30 seconds in a microreactor, with regioselectivity >98% and no polymer byproducts.

(3) PET probes: By replacing the precursor solution with ¹¹C-labeled MNU, ¹¹CH₂N₂ can be synthesized online and then reacted with drug intermediates to obtain ¹¹C-methylated products with radiochemical purity >95%. The total synthesis time was reduced from the traditional 90 minutes to 12 minutes, significantly reducing radioactive dose loss.

Microreactor technology transforms a highly explosive chemical, previously considered too dangerous to handle, into a continuously controllable and scalable engineering process. Its core principles can be summarized as follows:

(1) The "in-situ generation and immediate consumption" strategy completely overturns the traditional "prepare first, then use" model, eliminating cumulative risks at the source;

(2) "Enhanced mass and heat transfer" increases the reaction temperature from the traditional -50 ℃ to room temperature or even 50 ℃, significantly reducing energy consumption and equipment requirements;

(3) "Membrane separation and scale-up" provides the optimal balance between safety and production capacity, without increasing channel size or sacrificing surface area.