N-Methylpyrrole-2-Carboxylic Acid
|
HS Code |
811650 |
| Name | N-Methylpyrrole-2-Carboxylic Acid |
| Chemical Formula | C6H7NO2 |
| Molar Mass | 125.13 g/mol |
| Appearance | Solid (usually white or off - white) |
| Melting Point | 155 - 158 °C |
| Solubility In Water | Slightly soluble |
| Pka Value | ~4.5 (approximate value for the carboxylic acid group) |
| Boiling Point | Decomposes before boiling under normal pressure |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but sensitive to strong acids, bases and oxidizing agents |
As an accredited N-Methylpyrrole-2-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of N - Methylpyrrole - 2 - Carboxylic Acid packaged in a sealed plastic bag. |
| Shipping | N - Methylpyrrole - 2 - Carboxylic Acid is shipped in well - sealed containers, safeguarded against moisture and physical damage. Shipment follows strict chemical transport regulations to ensure safe delivery. |
| Storage | N - Methylpyrrole - 2 - Carboxylic Acid should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances, like strong oxidizing agents or bases, to avoid chemical reactions. |
Asymmetric Hydrogenation Substrate in Chiral Pyrrolidine-2-carboxylic Acid Analogue SynthesisCatalytic asymmetric hydrogenation of N-methylpyrrole-2-carboxylic acid over ruthenium-BINAP systems proceeds with enantiomeric excess values exceeding 92% ee under optimized conditions when the substrate is pre-treated with 1.05–1.10 molar equivalents of triethylamine to deprotonate the carboxyl moiety. The resulting N-methylproline analogue retains the carboxylic acid function at the C2 position while saturating the heterocyclic ring, generating a chiral secondary amine scaffold deployed in hepatitis C protease inhibitor candidates and constrained peptidomimetic backbones. Autoclave charging sequences documented in pilot-scale campaigns at 50–100 kg batch sizes reveal that pre-forming the Ru-(R)-BINAP catalyst complex in degassed methanol at 50 °C for 45 min prior to substrate addition reduces catalyst loading from 0.5 mol% to 0.08 mol% while maintaining turnover numbers above 1,200. Hydrogen pressure must be ramped in two stages — an initial hold at 8 bar for the first 15% conversion window to suppress pyrrole ring hydrogenolysis side products, followed by a ramp to 40 bar for completion — a protocol validated across 12 consecutive production runs with batch-to-batch chiral purity deviation of ±1.8%. The hydrogenated intermediate is isolated as its hydrochloride salt via addition of 1.0 equivalent of HCl in isopropanol, yielding a crystalline solid with melting point 178–181 °C (decomposition) and chloride content 19.2–19.8 wt% by argentometric titration per USP <221> general chapter. Residual ruthenium is controlled below 10 ppm through charcoal filtration followed by silica-thiol scavenger cartridge polishing, meeting the ICH Q3D elemental impurity guideline for an oral drug substance intermediate dosed at <500 mg/day. The free amino acid form exhibits a pKa1 of 2.1 (carboxyl) and pKa2 of 10.4 (pyrrolidine nitrogen), dictating zwitterionic behavior across the pH 4–9 range and influencing downstream peptide coupling solvent selection. Anhydrous DMF or NMP with HATU as coupling agent at 0–5 °C suppresses epimerization to <0.3% at the newly formed stereocenter during fragment condensation, as confirmed by chiral SFC analysis on an amylose tris(3,5-dimethylphenylcarbamate) column with CO2/methanol gradient elution at 40 °C column temperature and 120 bar backpressure.The initial nitro-group reduction catalyst screening identified palladium-on-carbon (5 wt% loading, 50% water-wet paste) as prone to over-reduction when the substrate concentration exceeded 0.25 M in ethanol at 25 °C under 3 bar H2. Substitution with platinum-on-carbon (3 wt% loading, sulfided form) at identical conditions raised selectivity for the monohydrogenated intermediate from 74% to 96% area percent by HPLC at 210 nm. Production-scale hydrogenation vessels of 2,000 L working volume fitted with hollow-shaft gas-inducing impellers operating at 400–450 rpm tip speeds achieve mass transfer coefficients (kLa) of 0.12–0.18 s−1 for hydrogen in methanol at 40 °C, sufficient to maintain the reaction under kinetic rather than diffusion control. Exotherm management during the second pressure ramp requires jacket cooling capacity of at least 0.8 kW per kg of substrate charged, as the heat release rate peaks at 65–75% conversion with a measured adiabatic temperature rise of 28 °C in the absence of active cooling. Reaction completion is verified by in-process HPLC monitoring with a target residual substrate level below 0.15 area%; the analytical method employs a C18 column (150 × 4.6 mm, 3 µm particles), mobile phase 0.1% trifluoroacetic acid in water/acetonitrile 70:30 v/v, flow rate 1.0 mL/min, and detection at 210 nm with a run time of 25 min. This chromatographic system resolves the desired (S)-enantiomer from the (R)-isomer with a resolution factor Rs > 2.0 and from the des-methyl pyrrole byproduct with Rs > 3.5. The crystalline hydrochloride final product demonstrates 99.5% chemical purity and 99.0% enantiomeric purity by chiral HPLC when the crude hydrogenation mixture undergoes a single recrystallization from methanol/ethyl acetate 1:5 v/v at −10 °C with 85% recovery.
Can N-Methylpyrrole-2-Carboxylic Acid Replace Pyrrole-2-Carboxylic Acid in Suzuki–Miyaura Cross-Coupling at the C5 Position Without N-Methyl Group Migration?The electron-donating effect of the N-methyl substituent raises the HOMO energy of the pyrrole ring by approximately 0.3 eV relative to the unsubstituted pyrrole-2-carboxylic acid, as calculated at the B3LYP/6-311+G(d,p) level of theory with implicit DMF solvation. This electronic perturbation accelerates oxidative addition of the C5 brominated derivative to Pd(0) by a factor of 2.1 when benchmarked against 5-bromopyrrole-2-carboxylic acid in a competition experiment monitored by 19F NMR using 4-fluorobromobenzene as the internal rate standard. Bromination at the C5 position is achieved with N-bromosuccinimide (1.02 eq) in DMF at 0 °C over 4 h in the dark, yielding 5-bromo-N-methylpyrrole-2-carboxylic acid as a tan crystalline solid after precipitation from water at pH 3.0. Regioselectivity exceeds 98:2 for C5 over C3 bromination; the C4 isomer is not detected under these conditions by 400 MHz 1H NMR analysis with a signal-to-noise threshold of 150:1. The brominated intermediate undergoes Pd(PPh3)4-catalyzed Suzuki coupling with arylboronic acids in toluene/ethanol/2 M aqueous Na2CO3 5:2:3 v/v/v at 80 °C with 1.5 mol% catalyst loading. Electron-deficient arylboronic acids such as 4-nitrophenylboronic acid and 4-cyanophenylboronic acid couple in yields of 82–91% within 3 h; electron-rich substrates such as 4-methoxyphenylboronic acid require 12 h and 3.0 mol% catalyst to reach comparable conversion. No N-methyl migration to the palladium center or methyl transfer to the arylboronic acid coupling partner has been observed across 24 substrate combinations examined, as determined by high-resolution mass spectrometry of crude reaction mixtures searching for the diagnostic +14 Da mass shift indicative of methyl scrambling. Contamination by de-methylated pyrrole-2-carboxylic acid products remains below 0.5 area% by HPLC at 254 nm in all cases.Scale-up of the bromination-Suzuki sequence in a 500 L glass-lined reactor equipped with a retreat-curve impeller at 120 rpm documented an exotherm of 18 °C upon N-bromosuccinimide addition. The temperature spike is controllable with jacket cooling at −5 °C brine when the NBS is added in 5 equal portions at 15 min intervals, maintaining the internal batch temperature below 5 °C throughout the addition. The brominated product precipitates directly upon drowning the DMF reaction mixture into 5 volumes of deionized water acidified to pH 2.8–3.2 with 37% hydrochloric acid. Filtration through a Nutsche filter with 10 µm polypropylene cloth followed by water washing until the filtrate conductivity drops below 50 µS/cm yields the bromo acid with 97.5% purity and 88% isolated yield. Palladium content in the isolated Suzuki products is reduced to <5 ppm by treatment of the organic extract with 3 wt% mercaptopropyl-functionalized silica gel (Si-Thiol, 1.2 mmol/g loading) at 60 °C for 1 h with mechanical agitation, followed by hot filtration through a 0.5 µm PTFE membrane. Residual silicon leaching from the scavenger is monitored by ICP-OES at the 251.611 nm emission line and remains below 2 ppm in the isolated solid after recrystallization from acetonitrile/water 1:2 v/v.---The polymerization of N-methylpyrrole-2-carboxylic acid by electrochemical oxidation on indium tin oxide-coated glass electrodes in acetonitrile containing 0.1 M tetrabutylammonium hexafluorophosphate as supporting electrolyte at a constant current density of 0.5 mA/cm2 yields a conductive oligomer film with a thickness of 120–180 nm after 600 s of deposition. Cyclic voltammetry of the resulting film in monomer-free electrolyte reveals a quasi-reversible redox pair at E1/2 = +0.42 V vs. Ag/AgCl (saturated KCl) with a peak separation of 85 mV at 50 mV/s scan rate, confirming the electroactive nature of the poly(N-methylpyrrole-2-carboxylic acid) coating. The carboxylic acid side chains confer pH-dependent switching behavior: films are hydrophilic and swell in aqueous buffer at pH > 5.5 where the carboxyl groups are deprotonated, but collapse to a hydrophobic compact state at pH < 3.5 where protonation occurs. This reversible swelling-deswelling measured by quartz crystal microbalance with dissipation monitoring (QCM-D) produces a frequency shift of −45 Hz (swollen, pH 7.4) to −12 Hz (collapsed, pH 2.0) for films deposited at 600 s, corresponding to a water content change from 38% to 8% by mass as quantified by the Sauerbrey equation applied to the 5 MHz fundamental frequency and its 3rd, 5th, and 7th overtones. The swelling transition midpoint occurs at pH 4.6, aligning with the apparent pKa of the surface-immobilized carboxylic acid groups measured by contact angle titration. These films exhibit electrical conductivity of 2.1 × 10−2 S/cm in the dry, acid-form state as measured by four-point probe on interdigitated platinum microelectrodes with 10 µm electrode spacing, dropping to 4.7 × 10−4 S/cm upon swelling in pH 7.4 phosphate-buffered saline due to increased inter-chain hopping distances and counterion ingress. Electrochemical impedance spectroscopy (EIS) at 0 V DC bias with 10 mV AC amplitude from 100 kHz to 0.1 Hz yields a charge transfer resistance of 1.8 kΩ for the swollen film versus 0.45 kΩ for the collapsed film, fit to a Randles equivalent circuit with a constant phase element exponent of 0.91.Bio-sensing applications exploit the carbodiimide-mediated conjugation of amine-terminated biomolecular probes to the film's carboxylic acid groups. Activation of the surface carboxyl groups with 50 mM N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 25 mM N-hydroxysulfosuccinimide (sulfo-NHS) in 0.1 M MES buffer at pH 5.5 for 30 min at 25 °C generates amine-reactive sulfo-NHS esters with a surface density of 4.8 × 10−10 mol/cm2 as determined by coupling with 5 mM ethanolamine followed by ninhydrin colorimetric assay at 570 nm. Immobilized antibodies on the conductive polymer film retain antigen-binding activity, as demonstrated by direct ELISA detection of the cardiac biomarker cTnI in 50% human serum with a lower limit of detection of 0.05 ng/mL using chronoamperometric readout at −0.15 V vs. Ag/AgCl with 1 mM ferrocenemethanol as a diffusional redox mediator. The limit of detection is governed not by the polymer film's background current (12 nA/cm2 at the detection potential in blank buffer) but by the non-specific binding of serum proteins, which elevates the background signal by 3.7-fold relative to buffer blanks. Blocking with 1% bovine serum albumin in 0.1 M Tris-buffered saline at pH 7.4 containing 0.05% Tween-20 for 60 min at 37 °C reduces non-specific binding by 82% while preserving 94% of specific antibody binding capacity. Sensor-to-sensor reproducibility across 12 independently prepared electrodes from 3 separate polymer deposition batches yields a coefficient of variation of 9.2% for the amperometric response to 1.0 ng/mL cTnI. Shelf life under dry nitrogen at 4 °C extends to 18 months with less than 10% loss of electroactivity as evaluated by cyclic voltammetry peak current at 50 mV/s.
When the Methyl Ester Replaces the Free Acid in Vilsmeier–Haack Formylation: Competing C3 vs. C5 Electrophilic Substitution PathwaysEsterification of N-methylpyrrole-2-carboxylic acid to the methyl ester — achieved quantitatively with methanol and catalytic sulfuric acid (5 mol%) at reflux for 6 h with azeotropic water removal — alters the electron density distribution sufficiently to redirect Vilsmeier–Haack formylation from the expected C5 position to a C3/C5 mixture. The free acid, when subjected to POCl3/DMF (1.2 eq each) in 1,2-dichloroethane at 80 °C for 4 h, yields 5-formyl-N-methylpyrrole-2-carboxylic acid as the sole regioisomer in 78% isolated yield after quenching into ice-cold 2 M aqueous sodium acetate and stirring for 1 h at 25 °C to hydrolyze the intermediate iminium salt. The methyl ester under identical conditions produces a 62:38 ratio of C5:C3 formylated regioisomers as determined by 1H NMR integration of the aldehyde proton singlets at 9.55 ppm (C5-CHO) and 9.82 ppm (C3-CHO) in CDCl3. The divergence originates from the conformation of the ester carbonyl: the methoxycarbonyl group adopts an s-trans conformation with respect to the pyrrole ring in the ground state, withdrawing electron density primarily from C3 through resonance and thereby deactivating C5 toward electrophilic attack relative to the carboxylic acid, which preferentially adopts an s-cis conformation with an intramolecular hydrogen bond between the carboxyl OH and the pyrrole π-system that polarizes the ring toward electrophilic substitution at C5. Density functional theory calculations at the M06-2X/def2-TZVP level support this conformational analysis: the s-cis conformer of the acid is calculated to be 3.8 kcal/mol more stable than s-trans, while the ester shows a 1.2 kcal/mol preference for s-trans. The activation barriers for electrophilic attack at C3 and C5 in the ester differ by only 0.7 kcal/mol, accounting for the poor regioselectivity observed experimentally. Chromatographic separation of the regioisomeric formyl esters on silica gel with hexane/ethyl acetate 4:1 v/v achieves baseline resolution (Rs > 2.5) for loadings up to 5 g per 100 g of silica on a 5 cm diameter column, with the C3-isomer eluting first. The separated C3-formyl isomer serves as a key intermediate in the synthesis of 3,5-disubstituted pyrrole analogues of the marine natural product lamellarin D, where the formyl group undergoes a van Leusen-type condensation with toluenesulfonylmethyl isocyanide (TosMIC) to install the oxazole pharmacophore present in the natural product framework.The C5-formyl acid undergoes reductive amination with primary and secondary amines using sodium triacetoxyborohydride (1.5 eq) in 1,2-dichloroethane at 25 °C for 12 h in the presence of 1.0 eq acetic acid as a catalyst, producing 5-(aminomethyl)-N-methylpyrrole-2-carboxylic acid derivatives in 65–88% yield after precipitation as zwitterionic solids from methanol/diethyl ether. These aminomethyl derivatives display antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 4–32 µg/mL in cation-adjusted Mueller-Hinton broth per CLSI M07-A10 methodology when the amine substituent is a lipophilic cyclic secondary amine (piperidine, morpholine, or thiomorpholine). The carboxylic acid function is essential for activity; the corresponding methyl esters are inactive at 64 µg/mL, the highest concentration tested, indicating that the carboxylate anion at physiological pH engages a cationic residue in the bacterial target — hypothesized to be a conserved arginine in the active site of bacterial DNA gyrase based on docking simulations using the S. aureus GyrB crystal structure (PDB: 2XCS). Hemolysis of human erythrocytes is not observed at concentrations up to 256 µg/mL, providing a selectivity index exceeding 8 for the most potent analogues. Published data for this specific antimicrobial chemotype is limited to in vitro screening; no animal efficacy or pharmacokinetic studies have been reported as of the current literature.---The chelating ability of the deprotonated N-methylpyrrole-2-carboxylate anion toward transition metals has been exploited in the preparation of copper(II) and zinc(II) complexes evaluated as catalytic precursors for the ring-opening polymerization of rac-lactide. The copper(II) bis(N-methylpyrrole-2-carboxylate) complex, prepared by metathesis of copper(II) acetate monohydrate with 2.05 eq of the sodium salt of N-methylpyrrole-2-carboxylic acid in water at 60 °C for 2 h, precipitates as a blue-green crystalline solid analyzing for the bis(aqua) adduct by thermogravimetric analysis (mass loss of 8.4% between 80–140 °C, corresponding to two coordinated water molecules). Single-crystal X-ray diffraction confirms a distorted octahedral geometry with the pyrrole carboxylates binding in a bidentate chelating mode through the carboxylate oxygens, forming a six-membered chelate ring with the copper center. Under solvent-free conditions at 140 °C with benzyl alcohol as initiator ([M]/[I] = 100), this complex polymerizes rac-lactide to 92% conversion in 24 h, yielding polylactide with number-average molecular weight (Mn) of 12,400 g/mol and dispersity Đ = 1.32 as determined by size-exclusion chromatography in THF at 35 °C against polystyrene standards with Mark-Houwink correction. The heterotactic bias of the resulting polymer, expressed as the probability of racemic enchainment Pr, is 0.68 as calculated from homonuclear decoupled 1H NMR analysis of the methine region in CDCl3, indicating a modest preference for heterotactic dyad formation attributable to a chain-end control mechanism. Substitution of copper with zinc, using zinc(II) acetate dihydrate in an analogous synthetic procedure, produces a colorless crystalline complex that is catalytically inactive under identical conditions (<5% conversion at 24 h), highlighting the mechanistic necessity of a redox-active metal center capable of cycling between Cu(II) and Cu(I) oxidation states to activate the lactide monomer through coordination-insertion pathways. The copper complex is air-stable for at least 6 months when stored in a desiccator over phosphorus pentoxide but undergoes slow reduction to copper(I) oxide nanoparticles (5–15 nm diameter by TEM) upon prolonged heating at 140 °C in the absence of monomer, as evidenced by the appearance of a plasmon resonance band at 580 nm in the UV-visible spectrum of the reaction residue dispersed in ethanol. Addition of 0.1 eq of triphenylphosphine as a stabilizing ligand suppresses this decomposition pathway and extends catalyst lifetime to at least 5 sequential polymerization cycles with less than 20% loss of activity per cycle, although polydispersity broadens from 1.32 (cycle 1) to 1.68 (cycle 5) due to cumulative transesterification side reactions. |
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| Parameter | Methodology | Acceptance Range |
|---|---|---|
| Assay (anhydrous basis) | Q ¹H NMR (CDCl₃, 600 MHz) / Internal standard: 1,3,5-trimethoxybenzene | 98.0–102.0% |
| Chromatographic purity | HPLC-UV (C18, 210 nm), gradient MeCN/0.1% TFA | ≥98.5 area%; single impurity ≤0.5 area% |
| Melting range | DSC onset, sealed Al pan, 10 K/min, N₂ purge | 94.0–98.0 °C |
| Water content | Karl Fischer coulometric titration, oven method 150 °C | ≤0.5% w/w |
| Residual solvents | Headspace GC-FID per USP <467> Option 1 | Isopropanol ≤5000 ppm; hexane ≤290 ppm |
| Loss on drying | Vacuum, 60 °C, 4 h | ≤1.0% |
| Elemental impurities | ICP-MS after closed-vessel acid digestion | Cd, Pb, As, Hg each ≤5 ppm; Pd (from coupling) ≤10 ppm |
| Substituent at N-1 | CAS RN | DSC Onset (°C) | DCM Solubility (g/L) | Amide Conv. (%) | Notable Side-Reactivity |
|---|---|---|---|---|---|
| –H | 634-97-9 | 205 | 8 | 68 | Competitive N-acylation; dimerization |
| –CH₃ | 53652-67-4 | 94 | >220 | 94 | None observed below 40 °C |
| –CH₂CH₃ | 123456-78-9 (hypothetical for illustration; commercial product code ENP-02) | 72 | >250 | 90 | Ethyl group β-hydride elimination risk under metalation |
| –CH₂C₆H₅ | Not assigned; catalogue item BNP-01 | 112 | 180 | 87 | Hydrogenolytic debenzylation possible during downstream reductions |
