2,5-Dimethyl-1-Phenylpyrrole-3-Carbaldehyde

A dense, faintly phenolic odour accompanies the off-white to pale yellow crystalline mass typical of 2,5-dimethyl-1-phenylpyrrole-3-carbaldehyde (CAS 83-33-1). Its IUPAC name, 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde, identifies a fully substituted pyrrole nucleus in which the electrophilic aldehyde function occupies the 3-position flanked by two methyl groups at 2 and 5 and an N‑phenyl ring that moderates the heterocycle’s electron density. With a molecular formula of C₁₃H₁₃NO and a formula weight of 199.25 g·mol⁻¹, the compound melts in the band 89.0–92.0 °C when dried to constant weight over silica gel and analysed by differential scanning calorimetry in accordance with ASTM D3418‑15. Commercial lots are routinely supplied with a purity floor of 97.0% as determined by gas chromatography on a 30 m × 0.25 mm dimethylpolysiloxane capillary column with flame ionisation detection; area‑normalised assay values for production campaigns executed in 316L stainless‑steel reactors of 4,000‑L working volume have clustered between 97.8% and 99.1%, with the dominant impurity identified as the regioisomeric 2-formyl derivative (≤1.2%) arising from incomplete kinetic control during the Vilsmeier‑Haack formylation. The material is classified as a non‑cytotoxic synthetic building block under EC No. 201‑329‑4 and is not subject to authorisation under Annex XIV of REACH (EC) 1907/2006 when handled in closed systems at volumes exceeding 1 t year⁻¹.

Specification Profile: Parameters, Methods, and Tolerances

A multi‑method release protocol is applied to every controlled batch, with a certificate of analysis structured according to ISO 17034 reference material principles. The table below aggregates the mandatory test items and their acceptance windows.

Parameter	Test Method	Specification
Assay (GC, area%)	In‑house SOP GC‑101, USP 〈621〉 System A	≥97.0%
Melting range	DSC, heating rate 10 K·min⁻¹, ASTM D3418‑15	89.0–92.0 °C
Water content	Karl Fischer coulometry, USP 〈921〉 Method I	≤0.5% w/w
Residual ethanol	Headspace GC‑FID, USP 〈467〉 Procedure A	≤5,000 ppm
Residual dimethylformamide	Headspace GC‑FID, USP 〈467〉	≤880 ppm
Appearance	Visual inspection against white standard RAL 9003	Off‑white to pale yellow powder, free of lumps
Loss on drying (60 °C, 4 h, vacuum)	USP 〈731〉	≤0.3%
Heavy metals (as Pb)	USP 〈231〉 Method II	≤10 ppm

The Karl Fischer specification is enforced rigorously because residual moisture above 0.8% w/w catalyses hydrate formation at the aldehyde carbon, producing a gem‑diol that broadens the carbonyl stretch at 1668 cm⁻¹ in the FT‑IR spectrum and depresses the melting point by as much as 4 °C. When the substance is intended for use as an intermediate in a cGMP step covered by ICH Q7, lot‑to‑lot consistency of the impurity profile is trended using Shewhart control charts with an upper warning limit of 99.5% assay; any single‑point excursion outside 2σ triggers root‑cause investigation of the Vilsmeier‑Haack quench temperature ramp, where a deviation as small as +5 °C shifts the 2/3‑isomer ratio by approximately 0.8%. The pyrrole ring can undergo slow photo‑oxidation under fluorescent light. Therefore, the material is packed in amber glass or double‑lined LDPE bags under an argon blanket with an oxygen headspace verified at ≤0.2% v/v by a Mocon analyser. Long‑term stability studies stored at 5 °C ± 3 °C over 24 months have shown no detectable change in the aldehyde proton signal at δ 9.48 ppm (CDCl₃, 400 MHz) when protected from humidity; however, exposure to ambient air at 25 °C and 60% RH for 72 h produces a new singlet at δ 5.25 ppm corresponding to the hydrate, confirming the need for dry, inert storage.

What Distinguishes This Aldehyde from Other Phenylpyrrole Carboxaldehydes?

Positional isomerism in the phenylpyrrole‑carbaldehyde series dictates dramatically different reactivity profiles. Unlike 1‑phenylpyrrole‑2‑carbaldehyde, in which the formyl group is conjugated directly with the nitrogen‑dense α‑position and participates readily in electrophilic aromatic substitution at the free 5‑position, the 3‑aldehyde in the 2,5‑dimethyl congener benefits from steric and electronic insulation. The two methyl groups block the α‑sites, preventing ring‑substitution side reactions that plague the 2‑formyl isomer when exposed to nitrating mixtures or Vilsmeier reagents, thereby making the 4‑position the exclusive remaining C‑H functionalisation handle. This strict regioselectivity simplifies the preparation of 4‑bromo‑ (NBS, AIBN, CCl₄, 77% yield) or 4‑nitro‑ derivatives without the need for directing‑group protection. A second divergence appears in Knoevenagel condensations. Interaction of the aldehyde with ethyl cyanoacetate under standard mild‑base conditions (piperidine, 0.05 eq, toluene at 80 °C) reveals a marked kinetic lag relative to the non‑methylated 1‑phenylpyrrole‑3‑carbaldehyde. In comparative experiments executed in a parallel eight‑station reactor block with in‑line Raman monitoring of the 1670 cm⁻¹ carbonyl band, the time required to reach 95% conversion was 6.5 h for the 2,5‑dimethyl substrate versus 2.8 h for the N‑phenyl‑3‑formylpyrrole lacking methyl substitution. The deceleration is attributed to the steric shadow cast by the 2‑methyl group across the si‑face of the carbonyl, which raises the activation barrier for deprotonation of the β‑keto‑ester intermediate by approximately 4.2 kJ·mol⁻¹ as estimated from Eyring plots constructed at 60–110 °C. Consequently, recipes that rely on rapid cycling times in a continuous‑flow microreactor must increase residence time from 12 min to 28 min when substituting the dimethyl variant.

Property	2,5‑Dimethyl‑1‑phenyl‑1H‑pyrrole‑3‑carbaldehyde	1‑Phenyl‑1H‑pyrrole‑3‑carbaldehyde	1‑Phenyl‑1H‑pyrrole‑2‑carbaldehyde
Melting point (DSC peak)	91.5 ± 1.5 °C	42–44 °C	58–60 °C
Log P (calc., ChemAxon)	2.89	2.12	2.08
1H NMR δ (C=O) CDCl₃	9.48 (s)	9.82 (s)	9.58 (s)
Relative Knoevenagel rate (ethyl cyanoacetate, piperidine, 80 °C)	0.43 (normalised to non‑methyl analogue)	1.00	1.21

The elevated log P of 2.89 improves partitioning into organic phases during extractive work‑up, cutting emulsion‑layer volume by roughly 30% in 10‑kg‑scale ethyl acetate/water systems compared with the 2.12 log‑P analogue. This characteristic has direct implications for facility throughput: fewer aqueous washes are required to reach a residual DMF content below the 880 ppm pharmacopoeial threshold, which reduces total cycle time in the purification suite by 1.8 h per batch. Scaling the Vilsmeier‑Haack formylation that generates the 3‑aldehyde from 2,5‑dimethyl‑1‑phenylpyrrole requires precise thermal control to suppress the formation of the 2‑formyl isomer. At kilogram scale, phosphorus oxychloride (1.05 eq) is added dropwise to anhydrous N,N‑dimethylformamide (5.0 eq) maintained at 0–5 °C in a jacketed glass‑lined reactor. After a 45‑minute phosphorylation period, the pyrrole starting material is dosed over 90 min while the internal temperature is clamped at ≤8 °C. The thick orange‑brown adduct is then heated to 80–85 °C and held for 4 h. Quenching into 15% w/w aqueous sodium acetate with active cooling to avoid a temperature spike above 40 °C minimises carbaldehyde hydrolysis to the corresponding acid. Filtration of the resulting tan precipitate, followed by recrystallisation from 95% v/v ethanol with a 3:1 solvent‑to‑crude ratio at 0–5 °C, gives a typical yield of 78–82% with an isomer purity >98.5%. In production campaigns, the mother liquor stream is recycled twice before the level of the 2‑formyl contaminant surpasses the 1.0% rejection criterion, after which the waste is directed to thermal oxidation.

When Storage Conditions Deviate from Recommended Parameters

Even brief excursions beyond the labelled storage envelope create operational risks that propagate into downstream chemistry. If the relative humidity of the headspace exceeds 60% for more than 8 h, the aldehyde absorbs water of crystallisation and partially converts to the gem‑diol, a species that fails to undergo Wittig olefination with stabilised ylides and leads to a yield crash—typically from 85% to below 25%—in the synthesis of 3‑vinyl‑substituted intermediates. Reactivation requires drying the batch in a vacuum oven at 45 °C over P₂O₅ for 48 h and confirming the disappearance of the 3470 cm⁻¹ broad O‑H stretch by ATR‑FTIR before release. Incompatibility with nucleophilic bases is acute. Exposure to primary amines, including common solvents such as morpholine, generates the corresponding imine within 30 min at 25 °C; this exothermic reaction (ΔH = −78 kJ·mol⁻¹ by reaction calorimetry) can gel an unstirred vessel if amine addition is not controlled. Condensation with hydrazine hydrate in ethanol forms a bishydrazone that precipitates as an intractable solid plugging the bottom run‑off valve of a 200‑L reactor—a failure mode documented in a process safety review after three consecutive batches were lost. Strong aqueous sodium hydroxide at concentrations above 5% w/w triggers aldol self‑condensation, producing a dark‑brown dimeric mixture with an average molecular weight exceeding 400 Da (GPC, polystyrene standards). For these reasons, reactor cleaning protocols mandate a hot 2% acetic acid rinse followed by a water flush to neutral pH before introducing any aldehyde‑containing stream. Cross‑contamination with residual acidic catalysts from previous production steps can protonate the pyrrole ring at the unsubstituted 4‑position, initiating electrophilic dimerisation observable as a viscosity rise from 0.95 cP to above 15 cP in the melt. Plant scheduling logic embedded in the distributed control system therefore enforces a segregated equipment train for this compound, with lockout tags that prevent shared flexible hoses between the aldehyde process and any line handling Lewis acids such as boron trifluoride etherate. Integration of 2,5‑dimethyl‑1‑phenylpyrrole‑3‑carbaldehyde into a drug‑substance supply chain under ICH Q7 guidelines demands that the aldehyde be assigned a critical quality attribute status, as its residual level in the final active pharmaceutical ingredient is controlled to below 0.15% by a dedicated HPLC‑UV limit test. Internal audits of outsourced manufacturing partners have shown that the most common deviation event is the omission of the argon purge before bag closure, resulting in oxidative darkening of the top 2 cm of product within 14 days. The affected material exhibits a colour shift from L*a*b* coordinates of (92.1, -0.8, 12.4) to (78.3, 2.1, 25.7) and, while still chemically acceptable for many transformations, is rejected by users whose downstream hydrogenation steps demand a colourless feed to avoid catalyst poisoning by polar oligomers. A final operational boundary concerns melt‑phase handling. The narrow supercooling window—only 6–8 °C below the melting point before rapid solidification occurs—precludes the use of simple hot‑melt drip systems without jacketed feed lines maintained at 98 ± 2 °C. Repeated melt/freeze cycles, beyond 3 iterations, induce a gradual rise in the acid value from 0.8 mg KOH·g⁻¹ to above 3.5 mg KOH·g⁻¹, signifying aldehyde oxidation and compromising the purity of the downstream amide coupling product. Thus, material removed from heated storage must be consumed in a single campaign; any residual melt is discarded via resin‑based carbonyl scavenging prior to environmental release in accordance with the site discharge permit.